Non-invasive vagal nerve stimulation to treat disorders

ABSTRACT

Devices, systems and methods are disclosed for treating bronchial constriction related to asthma, anaphylaxis, chronic obstructive pulmonary disease (COPD), exercise-induced bronchospasm and post-operative bronchospasm. The treatment comprises transmitting impulses of energy non-invasively to selected nerve fibers that activate neural pathways to reduce the release of acetycholine from airway-related vagal preganglionic neurons within the brain of the patient. The transmitted energy impulses, comprising magnetic and/or electrical energy, stimulate the selected nerve fibers to produce the bronchodilation.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. Nonprovisional applicationSer. No. 13/603,810 filed Sep. 5, 2012; which is a Continuation-in-Partof U.S. Nonprovisional application Ser. No. 13/222,087 filed Aug. 31,2011, which is a Continuation-in-Part of U.S. Nonprovisional applicationSer. No. 13/183,765 filed Jul. 15, 2011, now U.S. Pat. No. 8,874,227issued Oct. 28, 2014, which claims the benefit of U.S. ProvisionalApplication Ser. No. 61/488,208 filed May 20, 2011; which is aContinuation-in-Part to U.S. Nonprovisional application Ser. No.13/183,721 filed Jul. 15, 2011, now U.S. Pat. No. 8,676,324 issued Mar.18, 2014, which claims the benefit of U.S. Provisional Application Ser.No. 61/487,439 filed May 18, 2011; which is a Continuation-in-Part ofU.S. Nonprovisional application Ser. No. 13/109,250 filed May 17, 2011,now U.S. Pat. No. 8,676,330 issued Mar. 18, 2014, which claims thebenefit of U.S. Provisional Application Ser. No. 61/471,405 filed Apr.4, 2011; which is a Continuation-in-Part of U.S. Nonprovisionalapplication Ser. No. 13/075,746 filed Mar. 30, 2011, now U.S. Pat. No.8,874,205 issued Oct. 28, 2014, which claims the benefit of priority ofU.S. Provisional Application Ser. No. 61/451,259 filed Mar. 10, 2011;which is a Continuation-in-Part of U.S. Nonprovisional application Ser.No. 13/005,005 filed Jan. 12, 2011, now U.S. Pat. No. 8,868,177 issuedOct. 21, 2014; which is a Continuation-in-Part of U.S. Nonprovisionalapplication Ser. No. 12/964,050 filed Dec. 9, 2010, which claims thebenefit of U.S. Provisional Application Ser. No. 61/415,469 filed Nov.19, 2010; which is a Continuation-in-Part of U.S. Nonprovisionalapplication Ser. No. 12/859,568 filed Aug. 19, 2010; which is aContinuation-in-Part of U.S. Nonprovisional application Ser. No.12/408,131 filed Mar. 20, 2009, now U.S. Pat. No. 8,812,112 issued 19Aug. 2014; which is a Continuation-in-Part application of U.S.Nonprovisional application Ser. No. 12/612,177 filed Nov. 4, 2009, nowU.S. Pat. No. 8,041,428 issued Oct. 18, 2011; each of which isincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

The field of the present invention relates to the delivery of energyimpulses (and/or fields) to bodily tissues for therapeutic purposes. Theinvention relates more specifically to devices and methods for treatingconditions associated with bronchial constriction, including: asthma,anaphylaxis, chronic obstructive pulmonary disease (COPD),exercise-induced bronchospasm and post-operative bronchospasm. Theenergy impulses (and/or fields) that are used to treat those conditionscomprise electrical and/or electromagnetic energy, deliverednon-invasively to the patient.

The use of electrical stimulation for treatment of medical conditions iswell known. For example, electrical stimulation of the brain withimplanted electrodes has been approved for use in the treatment ofvarious conditions, including pain and movement disorders such asessential tremor and Parkinson's disease. Another application ofelectrical stimulation of nerves is the treatment of radiating pain inthe lower extremities by stimulating the sacral nerve roots at thebottom of the spinal cord [Paul F. WHITE, Shitong Li and Jen W. Chiu.Electroanalgesia: Its Role in Acute and Chronic Pain Management. AnesthAnalg 92(2001):505-513; U.S. Pat. No. 6,871,099 entitled Fullyimplantable microstimulator for spinal cord stimulation as a therapy forchronic pain, to Whitehurst, et al].

Another example of electrical stimulation for treatment of medicalconditions is vagus nerve stimulation (VNS, also known as vagal nervestimulation). It was developed initially for the treatment of partialonset epilepsy and was subsequently developed for the treatment ofdepression and other disorders. The left vagus nerve is ordinarilystimulated at a location within the neck by first surgically implantingan electrode there and then connecting the electrode to an electricalstimulator [U.S. Pat. No. 4,702,254 entitled Neurocybernetic prosthesis,to ZABARA; U.S. Pat. No. 6,341,236 entitled Vagal nerve stimulationtechniques for treatment of epileptic seizures, to OSORIO et al; U.S.Pat. No. 5,299,569 entitled Treatment of neuropsychiatric disorders bynerve stimulation, to WERNICKE et al; G. C. ALBERT, C. M. Cook, F. S.Prato, A. W. Thomas. Deep brain stimulation, vagal nerve stimulation andtranscranial stimulation: An overview of stimulation parameters andneurotransmitter release. Neuroscience and Biobehavioral Reviews 33(2009) 1042-1060; GROVES D A, Brown V. J. Vagal nerve stimulation: areview of its applications and potential mechanisms that mediate itsclinical effects. Neurosci Biobehav Rev 29(2005):493-500; Reese TERRY,Jr. Vagus nerve stimulation: a proven therapy for treatment of epilepsystrives to improve efficacy and expand applications. Conf Proc IEEE EngMed Biol Soc. 2009; 2009:4631-4634; Timothy B. MAPSTONE. Vagus nervestimulation: current concepts. Neurosurg Focus 25 (3, 2008):E9, pp. 1-4;ANDREWS, R. J. Neuromodulation. I. Techniques-deep brain stimulation,vagus nerve stimulation, and transcranial magnetic stimulation. Ann. N.Y. Acad. Sci. 993(2003): 1-13; LABINER, D. M., Ahern, G. L. Vagus nervestimulation therapy in depression and epilepsy: therapeutic parametersettings. Acta. Neurol. Scand. 115(2007): 23-33].

Many such therapeutic applications of electrical stimulation involve thesurgical implantation of electrodes within a patient. In contrast,devices used for the medical procedures that are disclosed herein do notinvolve surgery. Instead, the present devices and methods stimulatenerves by transmitting energy to nerves and tissue non-invasively. Amedical procedure is defined as being non-invasive when no break in theskin (or other surface of the body, such as a wound bed) is createdthrough use of the method, and when there is no contact with an internalbody cavity beyond a body orifice (e.g., beyond the mouth or beyond theexternal auditory meatus of the ear). Such non-invasive procedures aredistinguished from invasive procedures (including minimally invasiveprocedures) in that the invasive procedures insert a substance or deviceinto or through the skin (or other surface of the body, such as a woundbed) or into an internal body cavity beyond a body orifice.

For example, transcutaneous electrical stimulation of a nerve isnon-invasive because it involves attaching electrodes to the skin, orotherwise stimulating at or beyond the surface of the skin or using aform-fitting conductive garment, without breaking the skin [ThierryKELLER and Andreas Kuhn. Electrodes for transcutaneous (surface)electrical stimulation. Journal of Automatic Control, University ofBelgrade 18(2, 2008):35-45; Mark R. PRAUSNITZ. The effects of electriccurrent applied to skin: A review for transdermal drug delivery.Advanced Drug Delivery Reviews 18 (1996) 395-425]. In contrast,percutaneous electrical stimulation of a nerve is minimally invasivebecause it involves the introduction of an electrode under the skin, vianeedle-puncture of the skin. In what follows, comparison is sometimesmade between the disclosed noninvasive methods, versus comparableinvasive methods, for purposes of demonstrating feasibility and/orvalidation of the noninvasive methods.

Another form of non-invasive electrical stimulation is magneticstimulation. It involves the induction, by a time-varying magneticfield, of electrical fields and current within tissue, in accordancewith Faraday's law of induction. Magnetic stimulation is non-invasivebecause the magnetic field is produced by passing a time-varying currentthrough a coil positioned outside the body, inducing at a distance anelectric field and electric current within electrically conductingbodily tissue. The electrical circuits for magnetic stimulators aregenerally complex and expensive and use a high current impulse generatorthat may produce discharge currents of 5,000 amps or more, which ispassed through the stimulator coil to produce a magnetic pulse. Theprinciples of electrical nerve stimulation using a magnetic stimulator,along with descriptions of medical applications of magnetic stimulation,are reviewed in: Chris HOVEY and Reza Jalinous, The Guide to MagneticStimulation, The Magstim Company Ltd, Spring Gardens, Whitland,Carmarthenshire, SA34 0HR, United Kingdom, 2006. In contrast, themagnetic stimulators that are disclosed herein are relatively simplerdevices that use considerably smaller currents within the stimulatorcoils. Accordingly, they are intended to satisfy the need forsimple-to-use and less expensive non-invasive magnetic stimulationdevices, for use in treating bronchoconstriction, as well as use intreating other conditions.

Potential advantages of such non-invasive medical methods and devicesrelative to comparable invasive procedures are as follows. The patientmay be more psychologically prepared to experience a procedure that isnon-invasive and may therefore be more cooperative, resulting in abetter outcome. Non-invasive procedures may avoid damage of biologicaltissues, such as that due to bleeding, infection, skin or internal organinjury, blood vessel injury, and vein or lung blood clotting.Non-invasive procedures are generally painless and may be performedwithout the dangers and costs of surgery. They are ordinarily performedeven without the need for local anesthesia. Less training may berequired for use of non-invasive procedures by medical professionals. Inview of the reduced risk ordinarily associated with non-invasiveprocedures, some such procedures may be suitable for use by the patientor family members at home or by first-responders at home or at aworkplace. Furthermore, the cost of non-invasive procedures may besignificantly reduced relative to comparable invasive procedures.

In the present application, the non-invasive delivery of energy isintended ultimately to dilate constricted bronchial passages of thelung, by relaxing bronchial smooth muscle and/or inhibit mucousproduction by the mucous glands. The smooth muscles that line thebronchial passages are controlled by a confluence of vagus andsympathetic nerve fiber plexuses. Spasms of the bronchi during asthmaattacks, anaphylactic shock, and other pulmonary disorders can often bedirectly related to pathological signaling within these plexuses, asdescribed below.

Asthma, and other airway occluding disorders resulting from immuneresponses and inflammation-mediated bronchoconstriction, affects anestimated eight to thirteen million adults and children in the UnitedStates. A significant subclass of asthmatics suffers from severe asthma.An estimated 5,000 persons die every year in the United States as aresult of asthma attacks. Up to twenty percent of the populations ofsome countries are affected by asthma, estimated to be more than ahundred million people worldwide. Asthma's associated morbidity andmortality are rising in most countries despite the increasing use ofanti-asthma drugs.

Asthma is characterized as a chronic inflammatory condition of theairways. Typical symptoms are coughing, wheezing, tightness of the chestand shortness of breath. Asthma is a result of increased sensitivity toforeign bodies such as pollen, dust mites and cigarette smoke. The body,in effect, overreacts to the presence of these foreign bodies in theairways. As part of the asthmatic reaction, an increase in mucousproduction is often triggered, exacerbating airway restriction. Smoothmuscle surrounding the airways goes into spasm, resulting inconstriction of airways. The airways also become inflamed. Over time,this inflammation can lead to scarring of the airways and a furtherreduction in airflow. This inflammation leads to the airways becomingmore irritable, which may cause an increase in coughing and increasedsusceptibility to asthma episodes.

In general, there are three mechanisms that may be triggered in acuteasthma (and other conditions, such as anaphylaxis, as described below).First, allergens induce smooth muscle bronchoconstriction through Ig-Edependent release of mast cell mediators such as histamines,prostaglandins, and leukotrienes. Second, airway hyper-responsivenessresulting from local and central neural reflex stimulation and bymediators of inflammation can increase bronchoconstriction. A thirdmechanism may stimulate mucosal thickening and edematous swelling of thebronchial walls through increased microvascular permeability andleakage.

In the case of asthma, it appears that the airway tissue has both (i) ahypersensitivity to an allergen that causes the overproduction of thecytokines that stimulate the cholinergic receptors of the nerves and/or(ii) a baseline high parasympathetic tone or a high ramp-up to a strongparasympathetic tone when confronted with any level of cholinergiccytokine. The combination can be lethal. Anaphylaxis appears to bemediated predominantly by the hypersensitivity to an allergen causingthe massive overproduction of cholinergic receptor activating cytokinesthat overdrive the otherwise normally operating vagus nerve to signalmassive constriction of the airways. Drugs such as epinephrine driveheart rate up while also relaxing the bronchial muscles, effectingtemporary relief of symptoms from these conditions. Publications citedbelow show that severing the vagus nerve (an extreme version of reducingthe parasympathetic tone) has an effect similar to that of epinephrineon heart rate and bronchial diameter, in that the heart begins to race(tachycardia) and the bronchial passageways dilate.

Asthma is typically managed with inhaled medications that are takenafter the onset of symptoms, or by injected and/or oral medications thatare taken chronically. The medications typically fall into twocategories: those that treat the inflammation, and those that treat thesmooth muscle constriction. A first strategy is to provideanti-inflammatory medications, like steroids, to treat the airwaytissue, reducing the tendency of the airways to over-release themolecules that mediate the inflammatory process. A second strategy is toprovide a smooth muscle relaxant (e.g., an anticholinergic) to reducethe ability of the muscles to constrict. As treatments, anticholinergicsimprove lung function by modifying neural reflexes and parasympatheticvagal tone. While inferior to beta2-agonists as a primary treatment,inhaled anticholinergics are effective as an adjunct to beta2-agonistsand the combination offers an advantage in reducing hospital admissions.

It is sometimes advised that patients rely on anti-inflammatorymedications and avoidance of triggers, rather than on thebronchodilators, as their first line of treatment. For some patients,however, these medications, and even the bronchodilators areinsufficient to stop the constriction of their bronchial passages.Tragically, more than five thousand people suffocate and die every yearas a result of asthma attacks [NHLBI National Asthma Education andPrevention Program. Expert Panel Report 3 (EPR-3): Guidelines for theDiagnosis and Management of Asthma (NIH Publication No. 07-4051, RevisedAugust 2007). pp 1-417. NHLBI Health Information Center, P.O. Box 30105.Bethesda, Md. 20824-0105; Padmaja SUBBARAO, Piush J. Mandhane, MalcolmR. Sears. Asthma: epidemiology, etiology and risk factors. CMAJ 181(9,2009): E181-E190; Lee MADDOX and David A. Schwartz. The pathophysiologyof asthma. Annu. Rev. Med. 53(2002):477-98; ANDERSON G P. Endotypingasthma: new insights into key pathogenic mechanisms in a complex,heterogeneous disease. Lancet 372(9643, 2008): 1107-1119; CAIRNS C B.Acute asthma exacerbations: phenotypes and management. Clin Chest Med.27(1, 2006):99-108; RODRIGO G J. Predicting response to therapy in acuteasthma. Curr Opin Pulm Med. 15(1, 2009):35-38; Barbara P YAWN. Factorsaccounting for asthma variability: achieving optimal symptom control forindividual patients. Primary Care Respiratory Journal 17(3, 2008):138-147].

Anaphylaxis ranks among the other airway occluding disorders as the mostdeadly, claiming many deaths in the United States every year.Anaphylaxis (the most severe form of which is anaphylactic shock) is asevere and rapid systemic allergic reaction to an allergen. Minuteamounts of allergens may cause a life-threatening anaphylactic reaction.Anaphylaxis may occur after ingestion, inhalation, skin contact orinjection of an allergen. Anaphylactic shock usually results in death inminutes if untreated. It is a life-threatening medical emergency becauseof rapid constriction of the airway, resulting in brain damage throughoxygen deprivation.

The triggers for anaphylactic reactions range from foods (nuts andshellfish), to insect stings (bees), to medication (radio contrasts andantibiotics). It is estimated that 1.3 to 13 million people in theUnited States are allergic to venom associated with insect bites; 27million are allergic to antibiotics; and 5-8 million suffer foodallergies. In addition, anaphylactic shock can be brought on byexercise. Yet all such reactions are mediated by a series ofhypersensitivity responses that result in uncontrollable airwayocclusion driven by smooth muscle constriction, and dramatic hypotensionthat leads to shock. Cardiovascular failure, multiple organ ischemia,and asphyxiation are the most dangerous consequences of anaphylaxis.

Anaphylactic shock requires immediate advanced medical care. Currentemergency measures include rescue breathing, administration ofepinephrine, and/or intubation if possible. Rescue breathing may behindered by the closing airway but can help if the victim stopsbreathing on his own. Clinical treatment typically includesadministration of antihistamines (which inhibit the effects of histamineat histamine receptors, but which are usually not sufficient inanaphylaxis), and high doses of intravenous corticosteroids. Hypotensionis treated with intravenous fluids and sometimes vasoconstrictor drugs.For bronchospasm, bronchodilator drugs such as salbutamol areadministered [Phil LIEBERMAN. Epidemiology of anaphylaxis. CurrentOpinion in Allergy and Clinical Immunology 8(2008):316-320; Hugh A.SAMPSON et al. Second symposium on the definition and management ofanaphylaxis: Summary report—Second National Institute of Allergy andInfectious Disease/Food Allergy and Anaphylaxis Network symposium. JAllergy Clin Immunol 117(2006):391-397; Angela W TANG. A practical guideto anaphylaxis. Am Fam Physician 68(2003):1325-1332 and 1339-1340].

The number of people who are susceptible to anaphylactic responses isestimated to be more than 40 million in the United States. Given thecommon mediators of both asthmatic and anaphylactic bronchoconstriction,it is not surprising that asthma sufferers are at higher than averagerisk for anaphylaxis. Tragically, many of these patients are fully awareof the severity of their condition, but nevertheless die whilestruggling in vain to manage the attack medically. Many of these fatalincidents occur in hospitals or in ambulances, in the presence of highlytrained medical personnel who are powerless to break the cycle ofinflammation and bronchoconstriction (and life-threatening hypotensionin the case of anaphylaxis) affecting their patient. Unfortunately,prompt medical attention for anaphylactic shock and asthma are notalways available. For example, epinephrine is not always available forimmediate injection. Even in cases where medication and attention isavailable, life-saving measures are often frustrated because of thenature of the symptoms. Constriction of the airways frustratesresuscitation efforts, and intubation may be impossible because ofswelling of tissues. Typically, the severity and rapid onset ofanaphylactic reactions does not render the pathology amenable to chronictreatment, but requires more immediately acting medications. Epinephrineis among the most popular medications for treating anaphylaxis, commonlymarketed in so-called “Epipen” formulations and administering devices,which potential sufferers carry with them at all times. In addition toserving as an extreme bronchodilator, epinephrine raises the patient'sheart rate dramatically in order to offset the hypotension thataccompanies many reactions. This cardiovascular stress can result intachycardia, heart attacks and strokes.

Chronic obstructive pulmonary disease (COPD) is a major cause ofdisability and is the fourth leading cause of death in the UnitedStates. More than 12 million people are currently diagnosed with COPD.An additional 12 million likely have the disease but are unaware oftheir condition. COPD is a progressive disease that makes itincreasingly difficult for the patient to breathe. COPD can causecoughing that produces large amounts of mucus, wheezing, shortness ofbreath, chest tightness and other symptoms. Cigarette smoking is theleading cause of COPD, although long term exposure to other lungirritants, such as air pollution, chemical fumes or dust may alsocontribute to COPD. In COPD, there is abnormally low air flow within thebronchial airways for a variety of reasons, including loss of elasticityin the airways and/or air sacs, inflammation and/or destruction of thewalls between many of the air sacs and overproduction of mucus withinthe airways.

The term COPD includes two primary conditions: emphysema and chronicobstructive bronchitis. In emphysema, the walls between many of the airsacs are damaged, causing them to lose their shape and become floppy.This damage can also destroy the walls of the air sacs, leading to fewerand larger air sacs instead of many small ones. In chronic obstructivebronchitis, the patient suffers from permanently irritated and inflamedbronchial tissue that is slowly and progressively dying. This causes thelining to thicken and form thick mucus, making it difficult to breathe.Many of these patients also experience periodic episodes of acute airwayreactivity (i.e., acute exacerbations), wherein the smooth musclesurrounding the airways goes into spasm, resulting in furtherconstriction and inflammation of the airways. Acute exacerbations occur,on average, between two and three times a year in patients with moderateto severe COPD and are the most common cause of hospitalization in thesepatients, with mortality rates of approximately 11%. Frequent acuteexacerbations of COPD cause lung function to deteriorate quickly, andpatients never recover to the condition they were in before the lastexacerbation. As with asthma, current medical management of these acuteexacerbations is often insufficient [Dick D. BRIGGS Jr. Chronicobstructive pulmonary disease overview: prevalence, pathogenesis, andtreatment. J Manag Care Pharm 10(4 suppl S-a, 2004):53-510; MarcDECRAMER, Wim Janssens, Marc Miravitlles. Chronic obstructive pulmonarydisease. Lancet 379(2012): 1341-1351].

Exercise-induced bronchospasm (EIB) results from a transient increase inairway resistance that occurs five to ten minutes after initiation ofexercise. It produces symptoms such as shortness of breath, cough,wheezing, chest tightness, or pain. Eighty to ninety percent of patientswith asthma also have EIB, but up to a quarter of non-asthmatic athletesmay also experience EIB. The condition is usually treated withshort-acting bronchodilator medication, with or without the addition ofanti-inflammatory agents, taken 15 to 30 minutes before initiation ofexercise. However, many patients do not respond to those treatments, orthey experience unwanted side effects. Accordingly, one objective of thepresent invention is to provide an alternative to pharmacologicaltreatment, through the use of noninvasive vagal nerve stimulation beforeand/or after exercise [Taru SINHA and Alan K. David. Recognition andmanagement of exercise-induced bronchospasm. Am Fam Physician67(2003):769-774].

Bronchospasm is one of the most significant respiratory complicationsthat can occur during surgical anesthesia, and asthmatic patients, aswell as some patients with COPD, are at elevated risk for it. Becausethe beneficial effects of steroids on airway reactivity occurs over aperiod of hours, patients at risk of experiencing bronchospasm duringsurgery are sometimes treated with steroids starting 24-48 h beforesurgery. The patients who are actually wheezing before surgery alsoreceive treatment with inhaled beta-2 adrenergic agents andcorticosteroids. Such wheezing may also be experienced by patientswithout pre-existing reactive airway disease, due to pulmonary edema,pneumothorax, drug reactions, aspiration, and endobronchial intubation.If the pharmacological treatment does not stop or prevent the wheezing,the surgery may be deferred, but this is not always practical orpossible in view of the need for surgery. Accordingly, one objective ofthe present invention is to provide an alternative to pharmacologicaltreatment, through the use of noninvasive vagal nerve stimulation beforesurgery.

Despite precautions and pre-treatments, bronchospasm may neverthelessoccur during surgery, in which case, beta-2 adrenergic agents may alsobe administered through an endotracheal tube. For some patients, thoseagents may not be effective or are otherwise contraindicated, and thebronchospasm may continue even after the surgery is completed.Accordingly, another objective of the present invention is to provide analternative to pharmacological treatment for bronchospasm that occursduring and after surgery, through the use of noninvasive vagus nervestimulation [Peter ROCK and Preston B. Rich. Postoperative pulmonarycomplications. Current Opinion in Anaesthesiology 16(2003): 123-132].

Unlike cardiac arrhythmias, which can be treated chronically withpacemaker technology, or in emergent situations with defibrillators(implantable and external), there is no commercially available medicalequipment that can chronically reduce the baseline sensitivity of thesmooth muscle tissue in the airways, to reduce the predisposition toasthma attacks, to reduce the symptoms of COPD or to break the cycle ofbronchial constriction associated with an acute asthma attack oranaphylaxis. Therefore, there is a need in the art for new products andmethods for treating the immediate symptoms of bronchial constrictionresulting from pathologies such as anaphylactic shock, asthma, COPD,exercise-induced bronchospasm, and post-operative bronchospasm. Inparticular, there is a need in the art for non-invasive devices andmethods to treat the immediate symptoms of bronchial constriction.

Although energy has been applied previously to patients in such a way asto bring about bronchodilation, those investigations involve methodsthat are invasive. For example, U.S. Pat. No. 7,740,017, entitled Methodfor treating an asthma attack, to DANEK et al., discloses an invasivemethod for directing radio frequency energy to the lungs to bring aboutbronchodilation. U.S. Pat. No. 7,264,002, entitled Methods of treatingreversible obstructive pulmonary disease, to DANEK et al., disclosesmethods of treating an asthmatic lung invasively, by advancing atreatment device into the lung and applying energy. Those invasivemethods attempt to dilate the bronchi directly, rather than to stimulatenerve fibers that in turn bring about bronchodilation.

In contrast, the present invention discloses the use of noninvasiveelectrical stimulation of the vagus nerve (VNS) to dilate constrictedbronchi. U.S. Pat. No. 6,198,970, entitled Method and apparatus fortreating oropharyngeal respiratory and oral motor neuromusculardisorders with electrical stimulation, to FREED et al., describesnoninvasive electrical stimulation methods for the treatment of asthmaand COPD, but they involve direct stimulation of muscles instead of thevagus nerve. The present invention is unexpected because previousreports teach away from the use of (invasive or noninvasive) VNS totreat bronchoconstriction. Thus, in most subjects with asthma, vagalnerve activity contributes in varying degree to bronchoconstriction[OKAYAMA M, Yafuso N, Nogami H, et al. A new method of inhalationchallenge with propranolol: comparison with methacholine-inducedbronchoconstriction and role of vagal nerve activity. J Allergy ClinImmunol. 80(1987):291-9]. In fact, a clinical report suggests that vagalnerve stimulation may cause bronchoconstriction [BIJWADIA J S, Hoch R C,Dexter D D. Identification and treatment of bronchoconstriction inducedby a vagus nerve stimulator employed for management of seizure disorder.Chest 127(1, 2005):401-402]. Yet other reports list dyspnea or shortnessof breath as common side effects of VNS, which is contrary to theobjectives of the present invention [MORRIS G L 3rd, Mueller W M.Long-term treatment with vagus nerve stimulation in patients withrefractory epilepsy. The Vagus Nerve Stimulation Study Group E01-E05.Neurology 53(1999):1731-5; Su Jeong YOU, Hoon-Chul Kang, Heung Dong Kim,Tae-Sung Ko, Deok-Soo Kim, Yong Soon Hwang, Dong Suk Kim, Jung-Kyo Lee,Sang Keun Park. Vagus nerve stimulation in intractable childhoodepilepsy: a Korean multicenter experience. J Korean Med Sci22(2007):442-445; RUSH A J, Sackeim H A, Marangell L B, et al. Effectsof 12 months of vagus nerve stimulation in treatment-resistantdepression: a naturalistic study. Biol Psychiatry 58(2005):355-363].These clinical reports that VNS produces symptoms of bronchoconstrictionmay be understood from animal experiments that also teach away from theuse of VNS to treat bronchoconstriction [BLABER L C, Fryer A D, MaclaganJ. Neuronal muscarinic receptors attenuate vagally-induced contractionof feline bronchial smooth muscle. Br J Pharmacol 86(1985):723-728].

The vagus nerve innervates the heart, which raises additional concernsthat even if VNS could be used to dilate bronchi, such vagus nervestimulation could trigger cardiac or circulatory problems, includingbradycardia, hypotension, and arrhythmia, particularly if the rightvagus nerve is stimulated [SPUCK S, Tronnier V, Orosz I, Schönweiler R,Sepehrnia A, Nowak G, Sperner J. Operative and technical complicationsof vagus nerve stimulator implantation. Neurosurgery 67(2 SupplOperative, 2010):489-494; SPUCK S, Nowak G, Renneberg A, Tronnier V,Sperner J. Right-sided vagus nerve stimulation in humans: an effectivetherapy? Epilepsy Res 82(2008):232-234; THOMPSON G W, Levett J M, MillerS M, Hill M R, Meffert W G, Kolata R J, Clem M F, Murphy D A, Armour JA. Bradycardia induced by intravascular versus direct stimulation of thevagus nerve. Ann Thorac Surg 65(3, 1998):637-42; SRINIVASAN B, AwasthiA. Transient atrial fibrillation after the implantation of a vagus nervestimulator. Epilepsia 45(12, 2004):1645]. In fact, vasovagal reactionsare classically brought about by a triggering stimulus to the vagusnerve, resulting in simultaneous enhancement of parasympathetic nervoussystem (vagal) tone and withdrawal of sympathetic nervous system tone.

Accordingly, we performed experiments, which are described herein,showing first that invasive electrical stimulation of the vagus nervecan in fact produce bronchodilation without first producingbronchoconstriction [Thomas J. HOFFMANN, Steven Mendez, Peter Staats,Charles W. Emala, Puyun Guo. Inhibition of Histamine-InducedBronchoconstriction in Guinea Pig and Swine by Pulsed Electrical VagusNerve Stimulation. Neuromodulation 12(4, 2009): 261-269]. The success ofthose and subsequent experiments motivated the present disclosure thatnoninvasive methods and devices can also produce bronchodilation inhumans, provided that the disclosed special devices and stimulationmethods are used. Those devices and methods address not only theproblems of producing bronchodilation and avoiding the production ofabnormal heart rate or blood pressure, but also the problem ofstimulating at the skin of the patient in such a way that a vagus nerveis selectively modulated, and in such a way that side effects includingmuscle twitching and stimulation pain are minimized or avoided.

SUMMARY OF THE INVENTION

The present invention involves devices and methods for the treatment ofasthma, COPD, anaphylaxis, exercise-induced bronchospasm, post-operativebronchospasm, and other pathologies involving constriction of theprimary airways. It uses an energy source comprising magnetic and/orelectrical energy that is transmitted non-invasively to, or in closeproximity to, a selected nerve to temporarily stimulate, block and/ormodulate the signals in the selected nerve.

The present invention is particularly useful for the acute relief ofsymptoms associated with bronchial constriction, e.g., asthma attacks,COPD exacerbations and/or anaphylactic reactions. The teachings of thepresent invention provide an emergency response to such acute symptoms,by producing an almost immediate airway dilation, enabling subsequentadjunctive measures (such as the administration of epinephrine) to beeffectively employed. The invention may be useful for treatingbronchoconstriction in patients who cannot tolerate the side effects ofalbuterol or other short acting β-agonists, who do not gain sufficientbenefit from anticholinergic medications including tioproprium bromide,or whose airway resistance is too high to get adequate benefit frominhaled medications. In preferred embodiments, the disclosed methods anddevices do not produce clinically significant side effects, such aschanges in heart rate or blood pressure.

One aspect of the method includes stimulating, inhibiting, blocking orotherwise modulating nerves that directly or indirectly modulateparasympathetic ganglia transmission, by stimulation or inhibition ofpreganglionic to postganglionic transmissions. According to this featureof the invention, noninvasive vagus nerve stimulation with the discloseddevices can activate pathways causing release of norepinephrine,serotonin and GABA (inhibitory neurotransmitters) onto airway-relatedvagal preganglionic neurons (AVPNs), thereby preventing release ofacetylcholine in the airways, and resulting in bronchorelaxation. Theseneural pathways also innervate the mucous glands in the lungs and otherairway passages. Thus, the activation of these neural pathways alsoinhibits mucous production in the airways, increasing airflow to andfrom the patient's lungs.

In an alternative embodiment, the fibers responsible for bronchodilationare interneurons that are completely contained within the walls of thebronchial airways. These interneurons are responsible for modulating thecholinergic nerves in the bronchial passages. In this embodiment, theincreased activity of the interneurons will cause inhibition or blockingof the cholinergic nerves responsible for bronchial constriction,thereby facilitating opening of the airways.

In yet another aspect of the present invention, the selected nervefibers comprise those that send an afferent vagal signal to the brain,which then triggers an efferent sympathetic signal to stimulate therelease of catecholamines (comprising endogenous beta-agonists,epinephrine and/or norepinephrine) from the adrenal glands and/or fromnerve endings that are within the lung or distributed throughout thebody.

The stimulating step is preferably carried out without substantiallystimulating excitatory nerve fibers, such as parasympathetic cholinergicnerve fibers, that are responsible for increasing the magnitude ofconstriction of smooth muscle. In this manner, the activity of the nervefibers responsible for bronchodilation are increased without increasingthe activity of the cholinergic fibers, which would otherwise inducefurther constriction of the smooth muscle. Alternatively, the method maycomprise the step of actually inhibiting or blocking these cholinergicnerve fibers such that the nerves responsible for bronchodilation arestimulated while the nerves responsible for bronchial constriction areinhibited or completely blocked. This blocking/inhibiting signal may beseparately applied to the inhibitory nerves; or it may be part of thesame signal that is applied to the nerve fibers directly responsiblebronchodilation.

In yet another aspect of the present invention, stimulation of a vagusnerve randomizes afferent neural signals sent to the central nervoussystem, or it randomizes efferent signals sent from the central nervoussystem to the bronchi, thereby resetting the phase relations betweenbronchiole smooth muscle oscillators. A consequence of thisphase-resetting is that it promotes an avalanche-type reopening ofbronchioles within regions of the lung that had been poorly ventilated,or it prevents avalanche-type closing of bronchioles.

The method of treating bronchial constriction includes applying anenergy impulse to a target region in the patient, preferably over aperiod of less than two minutes, and acutely reducing the magnitude ofbronchial constriction in the patient. Preferably, the bronchodilationeffect lasts from about 2 to 8 hours.

The energy impulse is transmitted non-invasively from an energy source,comprising magnetic and/or electrical sources of energy. As used herein,the term “acutely” means that the energy impulse immediately begins tointeract with one or more nerves to produce a response in the patient.The energy impulse is preferably sufficient to promptly andquantitatively ameliorate a symptom, for example, to increase the ForcedExpiratory Volume in 1 second (FEV1) of the patient by a clinicallysignificant amount in a period of time less than about 6 hours,preferably less than 3 hours and more preferably less than 90 minutesand even more preferably less that 15 minutes. A clinically significantamount is defined herein as at least a 12% increase in the patient'sFEV1 versus the FEV1 measured prior to application of the energyimpulse. In an exemplary embodiment, the energy impulse is sufficient toincrease the FEV1 by at least 19% over the FEV1 as predicted.Preferably, the increase in FEV1 is accompanied by a clinicallysignificant improvement in Peak Expiratory Flow (PEF) and Work ofBreathing (WOB).

In one embodiment of the invention, the stimulator comprises a source ofelectrical power and two or more remote electrodes that are configuredto stimulate a deep nerve relative to the nerve axis. The stimulatorcomprises two electrodes that lie side-by-side within separatestimulator heads, wherein the electrodes are separated by electricallyinsulating material. Each electrode is in continuous contact with anelectrically conducting medium that extends from the interface elementof the stimulator to the electrode. The interface element also contactsthe patient's skin when the device is in operation.

Current passing through an electrode may be about 0 to 40 mA, withvoltage across the electrodes of about 0 to 30 volts. The current ispassed through the electrodes in bursts of pulses. There may be 1 to 20pulses per burst, preferably five pulses. Each pulse within a burst hasa duration of about 20 to 1000 microseconds, preferably 200microseconds. A burst followed by a silent inter-burst interval repeatsat 1 to 5000 bursts per second (bps, similar to Hz), preferably at 15-50bps, and even more preferably at 25 bps. The preferred shape of eachpulse is a full sinusoidal wave.

A source of power supplies a pulse of electric charge to the electrodesor magnetic stimulator coil, such that the electrodes or magneticstimulator produce an electric current and/or an electric field withinthe patient. The electrical or magnetic stimulator is configured toinduce a peak pulse voltage sufficient to produce an electric field inthe vicinity of a nerve such as a vagus nerve, to cause the nerve todepolarize and reach a threshold for action potential propagation. Byway of example, the threshold electric field for stimulation of thenerve may be about 8 V/m at 1000 Hz. For example, the device may producean electric field within the patient of about 10 to 600 V/m (preferablyless than 100 V/m) and an electrical field gradient of greater than 2V/m/mm. The electric fields produced by the present invention at thevagus nerve are generally sufficient to excite all myelinated A and Bfibers, but not the unmyelinated C fibers. However, by using a reducedamplitude of stimulation, excitation of A-delta and B fibers may also beavoided.

The preferred stimulator shapes an elongated electric field of effectthat can be oriented parallel to a long nerve, such as a vagus. Byselecting a suitable waveform to stimulate the nerve, along withsuitable parameters such as current, voltage, pulse width, pulses perburst, inter-burst interval, etc., the stimulator produces acorrespondingly selective physiological response in an individualpatient, such as bronchodilation. Such a suitable waveform andparameters are simultaneously selected to avoid substantiallystimulating nerves and tissue other than the target nerve, particularlyavoiding the stimulation of nerves that produce pain.

Treating or averting of an exacerbation of bronchoconstriction may alsobe implemented within the context of control theory. A controllercomprising, for example, one of the disclosed vagus nerve stimulators, aPID, and a feedforward model, provides input to the patient viastimulation of one or both of the patient's vagus nerves. Feedforwardmodels may be grey-box models that incorporate knowledge of the bronchiand their physiological control. They may also be black box models,particularly models that make use of support vector machines. Data forexercising the models are from noninvasive physiological and/orenvironmental signals obtained from sensors located on or about thepatient. A grey-box model involving coupled Duffing oscillators thatmodels bronchial smooth muscle dynamics is disclosed. The model predictsthe abrupt onset of asthma, and its abrupt termination through use ofvagus nerve stimulation, which is described in terms of phase diagrams.

The novel systems, devices and methods for treating bronchialconstriction are more completely described in the following detaileddescription of the invention, with reference to the drawings providedherewith, and in claims appended hereto. Other aspects, features,advantages, etc. will become apparent to one skilled in the art when thedescription of the invention herein is taken in conjunction with theaccompanying drawings.

INCORPORATION BY REFERENCE

Hereby, all issued patents, published patent applications, andnon-patent publications that are mentioned in this specification areherein incorporated by reference in their entirety for all purposes, tothe same extent as if each individual issued patent, published patentapplication, or non-patent publication were specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purposes of illustrating the various aspects of the invention,there are shown in the drawings forms that are presently preferred, itbeing understood, however, that the invention is not limited by or tothe precise data, methodologies, arrangements and instrumentalitiesshown, but rather only by the claims.

FIG. 1 shows a cross-section of a bronchial lumen that is innervated byafferent and efferent nerve fibers of a vagus nerve that is electricallystimulated in the present invention, as well as a diagram ofbrain/brainstem structures that participate in the nervous control ofbronchial smooth muscle.

FIGS. 2A-2B show a plurality of schematic views of a plurality of nervemodulating devices, according to the present invention, which supplycontrolled pulses of electrical current to a magnetic stimulator coilshown in FIG. 2A or to surface electrodes shown in FIGS. 2B-2E whichshow an exemplary electrical voltage/current profile and waveform forstimulating, blocking and/or modulating impulses that are applied to anerve.

FIGS. 3A-3C respectively show a guinea pig's airway pressure as afunction of time, wherein at four time points, bronchoconstriction wasinduced using a brief histamine challenge, with and without vagus nervestimulation; the results of a succession of such challenges in a singleanimal; and the corresponding results for 16 different animals.

FIGS. 4A-4D disclose data from a guinea pig experiment showing thatwithout propranolol pretreatment, the effect of vagus nerve stimulationwas to reduce the magnitude of bronchoconstriction produced byhistamine, but when propranolol was administered as a pretreatment, theVNS-mediated attenuation of bronchoconstriction was blocked, as shown inFIGS. 4A-4B; and ligating vagus nerves between the stimulator electrodesand the brainstem blocks the attenuation of bronchoconstriction, asshown in FIGS. 4C-4D, as compared with the situation prior to ligation.

FIG. 5 shows data from a dog experiment demonstrating that noninvasivevagus nerve stimulation results in a significant reduction inmethacholine-induced bronchoconstriction at a succession of time points,which is comparable to results obtained with a high-dose of thebronchodilator drug albuterol.

FIGS. 6A-6E illustrate a dual-toroid magnetic stimulator coil accordingto an embodiment of the present invention, which is shown to be situatedwithin a housing that contains electrically conducting material, as perFIGS. 6A-6D, and the housing and cap of the dual-toroid magneticstimulator attached via cable to a box containing the device's impulsegenerator, control unit, and power source, as per FIG. 6E.

FIGS. 7A-7D illustrate a dual-electrode stimulator according to anembodiment of the present invention, which is shown to house thestimulator's electrodes and electronic components, as per FIGS. 7A-7B,as well as showing details of the head of the dual-electrode stimulator,as per FIGS. 7C-7D.

FIGS. 8A-8D illustrate an alternate embodiment of the dual-electrodestimulator, as per FIGS. 8A-8C, also comparing the dual-electrodestimulator with an embodiment of the magnetic stimulator, as per FIG.8D, according to the present invention.

FIG. 9 illustrates an approximate position of the housing of thestimulator according one embodiment of the present invention, when usedto stimulate the right vagus nerve in the neck of a patient.

FIG. 10 illustrates a housing of the stimulator according to oneembodiment of the present invention, when positioned to stimulate avagus nerve in the patient's neck, wherein the stimulator is applied tothe surface of the neck in the vicinity of the identified anatomicalstructures.

FIGS. 11A-11B show that vagus nerve stimulation improved both FEV1, asper FIG. 11A, and work, as per FIG. 11B, of breathing among twenty-fourbronchoconstricted asthma patients who failed to respond to one hour ofstandard medication.

FIGS. 12A-12E show that after 90 seconds of noninvasive vagus nervestimulation, thirty asthma patients showed an increase in FEV1,improvement in Peak Expiratory Flow, reduction in work of breathing VASscore, and no significant changes in heart rate or systolic or diastolicblood pressure.

FIG. 13 is a table showing a medication intake prior to and afternoninvasive vagus nerve stimulation, among six bronchoconstrictedpatients who appeared in an emergency department and who were stimulatedtwo times, 30 minutes apart, for 90 seconds each.

FIGS. 14A-14B show FEV1 and Work of Breathing VAS data as a function oftime, for six bronchoconstricted patients who appeared in an emergencydepartment and whose vagus nerves were stimulated two times, 30 minutesapart, for 90 seconds each.

FIG. 15 illustrates connections between a controller and a controlledsystem according to the present invention, their input and outputsignals, and external signals from the environment.

FIGS. 16A-16B illustrate a phase diagram according to the presentinvention, which circumscribes regions where coupled nonlinear bronchialoscillators exhibit qualitatively different types of dynamics, as afunction of the concentration of environmental irritants and of thecumulative magnitude of vagus nerve stimulation.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Once air is inhaled through the mouth or nose, it travels through thetrachea and a progressively bifurcating system of bronchi (containingcartilage) and bronchioles (which contain little or no cartilage), untilit finally reaches the alveoli, where the gas exchange of carbon dioxideand oxygen takes place. Through constriction or relaxation of smoothmuscle within their walls, the bronchioles change diameter to eitherreduce or increase air flow. The bronchioles between the fourth andeighth bifurcation are thought to be most important in that regard.Normally, an increase in diameter (bronchodilation) to increase air flowis stimulated by circulating epinephrine (adrenaline) or sympatheticnerve fibers or so-called iNANC nerve fibers, and a decrease in diameter(bronchoconstriction) is stimulated by parasympathetic cholinergic nervefibers, histamine, cold air, and chemical irritants. Reflexes haveevolved to regulate the caliber of bronchioles, in which afferent nervessend state-dependent sensory signals to the central nervous system,which in turn sends efferent controlling signals back to the bronchi andbronchioles, thereby allowing smooth muscle (and other components) inthe bronchi to adapt their caliber as needed to respond to such thingsas exercise, air-borne irritants, and infectious agents.

The present invention teaches non-invasive devices and methods fortreating abnormal bronchial constriction, by stimulating selected nervefibers that are responsible for reducing the magnitude of constrictionof smooth bronchial muscle, such that the activity of those selectednerve fibers is increased and smooth bronchial muscle is dilated. Inparticular, the present invention provides methods and devices forimmediate relief of acute symptoms associated with bronchialconstriction such as asthma attacks, COPD exacerbations, anaphylacticreactions, exercise-induced bronchospasm, and post-operativebronchospasm. The stimulated nerve fibers are particularly thoseassociated with a vagus nerve (tenth cranial nerve).

In a preferred embodiment, electrodes applied to the skin of the patientgenerate currents within the tissue of the patient. An objective of theinvention is to produce and apply electrical impulses that interact withthe signals of one or more nerves to achieve the therapeutic result ofbronchodilation. Much of the disclosure will be directed specifically totreatment of a patient by stimulation in or around a vagus nerve, withdevices positioned non-invasively on or near a patient's neck. Inparticular, the present invention can be used to directly or indirectlystimulate or otherwise modulate nerves that innervate bronchial smoothmuscle. However, it will be appreciated that the devices and methods ofthe present invention can be applied to other tissues and nerves of thebody, including but not limited to other parasympathetic nerves,sympathetic nerves, spinal or cranial nerves.

The methods described herein of applying an impulse of energy to aselected region of a vagus nerve may be refined to propagate signalsdirectly, or indirectly via the central nervous system, to at least oneof the anterior bronchial branches of a vagus nerve, or alternatively toat least one of the posterior bronchial branches thereof. Preferably thepropagated impulse is provided to at least one of the anterior pulmonaryor posterior pulmonary plexuses aligned along the exterior of the lung.As necessary, the impulse may be directed to nerves innervating only thebronchial tree and lung tissue itself. In addition, the impulse may bedirected to a region of the vagus nerve to stimulate, block and/ormodulate both the cardiac and bronchial vagal branches. As recognized bythose having skill in the art, this embodiment should be carefullyevaluated prior to use in patients known to have preexisting cardiacissues.

Topics that are presented below in connection with the disclosure of theinvention include the following:

(1) Overview of physiological mechanisms by which vagus nervestimulation may modulate bronchial smooth muscle, e.g., bring aboutbronchodilation;

(2) Description of Applicant's magnetic and electrode-based nervestimulating/modulating devices, describing in particular the electricalwaveform that is used to stimulate a vagus nerve;

(3) Applicant's animal experiments demonstrating that the disclosedstimulation waveform and devices may bring about bronchodilation byparticular physiological mechanisms;

(4) Preferred embodiments of the magnetic stimulator;

(5) Preferred embodiments of the electrode-based stimulator;

(6) Application of the stimulators to the neck of the patient;

(7) Measurements that are used to evaluate the state of a patient'sbronchoconstriction;

(8) Clinical experiments demonstrating that the disclosed stimulationwaveform and devices bring about bronchodilation in humans withoutsignificant adverse events;

(9) Use of the devices with feedback and feedforward to improvebronchodilation of individual patients;

(10) Nonlinear feedforward model of bronchial oscillations, and the useof VNS to reverse bronchial-closing avalanches in asthma.

Overview of Physiological Mechanisms by which Vagus Nerve StimulationMay Bring about Bronchodilation

A vagus nerve is composed of motor and sensory fibers. The vagus nerveleaves the cranium and is contained in the same sheath of dura matterwith the accessory nerve. The vagus nerve passes down the neck withinthe carotid sheath to the root of the neck. The branches of distributionof the vagus nerve include, among others, the superior cardiac, theinferior cardiac, the anterior bronchial and the posterior bronchialbranches. On the right side, the vagus nerve descends by the trachea tothe back of the root of the lung, where it spreads out in the posteriorpulmonary plexus. On the left side, the vagus nerve enters the thorax,crosses the left side of the arch of the aorta, and descends behind theroot of the left lung, forming the posterior pulmonary plexus.

A vagus nerve in man consists of over 100,000 nerve fibers (axons),mostly organized into groups. The groups are contained within fasciclesof varying sizes, which branch and converge along the nerve, and whichare surrounded by perineurium, epineurium, and fibrotic connectivetissue. Each fiber normally conducts electrical impulses only in onedirection, which is defined to be the orthodromic direction, and whichis opposite the antidromic direction. Besides efferent output fibersthat convey signals to the various organs in the body from the centralnervous system, the vagus nerve conveys sensory information about thestate of the body's organs back to the central nervous system. Some80-90% of the nerve fibers in the vagus nerve are afferent (sensory)nerves communicating the state of the viscera to the central nervoussystem.

The largest nerve fibers within a left or right vagus nerve areapproximately 20 μm in diameter and are heavily myelinated, whereas onlythe smallest nerve fibers of less than about 1 μm in diameter arecompletely unmyelinated. When the distal part of a nerve is electricallystimulated, a compound action potential is recorded by an electrodelocated more proximally. A compound action potential contains severalpeaks or waves of activity that represent the summated response ofmultiple fibers having similar conduction velocities. The waves in acompound action potential represent different types of nerve fibers thatare classified into corresponding functional categories, withapproximate diameters as follows: A-alpha fibers (afferent or efferentfibers, 12-20 μm diameter), A-beta fibers (afferent or efferent fibers,5-12 μm), A-gamma fibers (efferent fibers, 3-7 μm), A-delta fibers(afferent fibers, 2-5 μm), B fibers (1-3 μm) and C fibers(unnnyelinated, 0.4-1.2 μm). The diameters of group A and group B fibersinclude the thickness of the myelin sheaths.

In mammals, two vagal components have evolved in the brainstem toregulate peripheral parasympathetic functions. The dorsal vagal complex(DVC), consisting of the dorsal motor nucleus (DMNX) and itsconnections, controls parasympathetic function primarily below the levelof the diaphragm, while the ventral vagal complex (VVC), comprised ofnucleus ambiguus and nucleus retrofacial, controls functions primarilyabove the diaphragm in organs such as the heart, thymus and lungs, aswell as other glands and tissues of the neck and upper chest, andspecialized muscles such as those of the esophageal complex.

The parasympathetic portion of the vagus innervates ganglionic neuronswhich are located in or adjacent to each target organ. The VVC appearsonly in mammals and is associated with positive as well as negativeregulation of heart rate, bronchial constriction, bronchodilation,vocalization and contraction of the facial muscles in relation toemotional states. Generally speaking, this portion of the vagus nerveregulates parasympathetic tone. The VVC inhibition is released (turnedoff) in states of alertness. This, in turn, causes cardiac vagal tone todecrease and airways to open, to support responses to environmentalchallenges.

The parasympathetic tone is balanced in part by sympatheticinnervations, which generally speaking supplies signals tending to relaxthe bronchial muscles, so that over-constriction does not occur.Overall, airway smooth muscle tone is dependent on several factors,including parasympathetic input, inhibitory influence of circulatingepinephrine, iNANC nerves and sympathetic innervations of theparasympathetic ganglia. Stimulation of certain nerve fibers of thevagus nerve (up-regulation of tone), such as occurs in asthma or COPDattacks or anaphylactic shock, results in airway constriction and adecrease in heart rate. In general, the pathology of severe asthma, COPDand anaphylaxis appear to be mediated by inflammatory cytokines thatoverwhelm receptors on the nerve cells and cause the cells to massivelyupregulate the parasympathetic tone.

The role of a vagus nerve in controlling the caliber of a bronchus orbronchiole lumen is illustrated in FIG. 1. The bronchus or bronchiole istubular in shape, and the left side of FIG. 1 shows a cross-section ofits anatomy, viewed left-to-right from its central air-containing lumento its periphery. The figure as drawn is a composite of structures thatare found in large bronchi to small bronchioles, and it is not intendedto be a complete representation of the bronchioles and their control.The air in the lumen is in contact with a layer of mucus 101. That layercomprises water and various macromolecular glycoproteins disposed in agel/sol structure. It may also contain trapped inhaled particles andcells that participate in an immune response to inhaled viruses,bacteria and other antigens. The mucus is produced by cells in and nearthe epithelial layer 105 that lines the inner surface of the airway. Theepithelium of the larger airways comprises ciliated, basal, goblet,brush, and small-granule cells, among which the goblet cells areresponsible for much of the mucus. Larger airways also contain glands110 that contain two secretory cell types: the serous and the mucouscell, secretions from which reach the lumen via a duct inserted throughthe epithelium 105. The epithelium of the distal airways consists mainlyof ciliated and bronchiolar exocrine (Clara) cells, and the latter cellsproduce much of the mucus there. Transport of the mucus to the mouth isdue to ciliary beating of ciliated cells of the epithelium 105 and toairflow.

A basement membrane 115 anchors the epithelium 105 to loose connectivetissue that lies beneath the membrane. The lamina propria 120 is thelayer of connective tissue that lies immediately beneath the epithelium,which together with the epithelium constitutes the mucosa (or mucousmembrane) 125.

Cells that participate in host defense are present in the lamina propria120, such as cells of the innate- and adaptive-immune systems, includingmacrophages, neutrophils, eosinophils, dendritic cells, mast cells,natural killer cells, and lymphocytes. Those immune cells 130,interacting with the epithelial cells 105, are responsible for much ofthe defensive properties of the airways [Nicholas A. EISELE and DeborahM. Anderson. Host defense and the airway epithelium: frontline responsesthat protect against bacterial invasion and pneumonia. Journal ofPathogens 2011:249802, pp. 1-15; Laurent P. NICOD. Pulmonary defensemechanisms. Respiration 66(1999):2-11].

Variable amounts of elastin may also be present in the lamina propria120, or the elastin may appear as a layer 135 under a generallyseparated or discontinuous circumferential layer of smooth muscle 140.Contraction and relaxation of the smooth muscle 140 modulates thediameter of the bronchiole and its lumen, which thereby modulates theflow of air between the trachea and the alveoli, where gas exchangeoccurs.

Capillaries or other small blood vessels 145 are also present in thelamina propria 120, and blood vessels 145 (arteries and veins, e.g.venules) occupy the region of adventitia 150 between the smooth musclelayer 140 and the peripheral site of bronchiolar attachment 155 toalveoli or other lung structure such as cartilage [John WIDDICOMBE. Theairway vasculature. Experimental Physiology 78(1993):433-452].

Afferent nerve fibers 160 within the bronchi and bronchioles sense thestatus of the airways and send that information towards the centralnervous system. The brainstem and other central nervous tissue in turnprocess and integrate that information, along with information sensedfrom other lung structures and other organs (e.g., respiratory muscles,vasculature, heart, etc.), then send control signals along efferentnerve fibers 165 to directly or indirectly modulate the activity ofstructures within the bronchi and bronchioles. Thoseneuronally-modulated structures are primarily the smooth muscle 140 andthe secretion glands 110, but the blood vessels 145, the immune cells130 within the lamina propria, and cells within the epithelium 105 maybe modulated as well.

Although both the sympathetic and parasympathetic branches of theautonomic nervous system innervate the airways, the parasympatheticbranch dominates, especially with respect to control of airway smoothmuscle and secretions. Parasympathetic tone in the airways is regulatedby reflex activity often initiated by activation of airway stretchreceptors and polymodal nociceptors, as now described [Marie-ClaireMICHOUD. Neurohumoral control of the airways. Chapter 30, pp. 363-370In: Physiologic Basis of Respiratory Disease. Q Hamid, S Shannon and JMartin, eds. Hamilton, Ontario: BC Decker, 2005; BARNES P J. Modulationof neurotransmission in airways. Physiol Rev 1992; 72:699-729].

The afferent parasympathetic nerve fibers are typically subclassified aslow threshold mechanosensors and nociceptive-like fibers(slow-conducting, capsaicin-sensitive bronchopulmonary C fibers). Thelow threshold mechanosensors can be further subclassified as slowly(SAR) and rapidly (RAR) adapting stretch receptors. Less populousreceptor types, e.g. those that respond particularly to punctatemechanical stimulation or rapid changes in pH, also exist [Michael J.CARR and Bradley J. Undem. Bronchopulmonary afferent nerves. Respirology8(2003):291-301; Thomas TAYLOR-CLARK and Bradley J. Undem. Transductionmechanisms in airway sensory nerves. J Appl Physiol 101(2006):950-959;Giuseppe Sant' AMBROGIO. Nervous receptors of the tracheobronchial tree.Ann. Rev. Physiol. 49(1987):611-627].

SARs lie in close association with airway smooth muscle and respond tostretch of the airway wall. Some fire throughout the respiratory cycleand others burst in response to lung inflation, with progressiveincreases in discharge rate as a function of lung volume.

RARs are found throughout the tracheobronchial tree, primarily in andunder the epithelium and in close approximation to bronchial venules.They are exquisitely sensitive to mechanical stimuli and respond with arapidly adapting discharge to large and rapid lung inflations anddeflations. RARs are also stimulated or sensitized by intraluminalchemical irritants, smoke, dust, and environmental toxins. Because ofthe latter properties they are also known as irritant receptors.

Bronchial C-fiber receptors, which are innervated by nonmyelinated vagalafferent fibers, lie in the walls of the conducting airways. Theirendings extend into the space between epithelial cells or form a plexusimmediately beneath the basement membrane. The nociceptive nerves aremore responsive to chemical mediators than the stretch-sensitive RAR andSAR fibers (e.g., nicotine, acids, histamine, serotonin, bradykinin, andother mediators of inflammation). The C fibers are often referred to as“polymodal” fibers, because they respond to a broad range of stimuli.Activation of sensory C fiber receptors in the airways mucosa sets upaxon reflexes with release of sensory neuropeptides. These neuropeptidescause vasodilatation, possibly with edema and plasma exudation,submucosal gland secretion, structural and functional changes in theepithelium, and possibly airway smooth muscle contraction [M. KOLLARIK,F. Rua, M. Brozmanova. Vagal afferent nerves with the properties ofnociceptors. Autonomic Neuroscience: Basic and Clinical 153(2010):12-20].

The majority of afferent parasympathetic innervation to the lowerairways is carried by the vagus nerves (See FIG. 1). The vagal afferentnerve fibers arise from cell bodies located in the vagal sensoryganglia. These ganglia take the form of swellings found in the cervicalaspect of the vagus nerve just caudal to the skull. There are two suchganglia, termed the inferior and superior vagal ganglia. They are alsocalled the nodose and jugular ganglia, respectively (See FIG. 1). Thejugular (superior) ganglion is a small ganglion on the vagus nerve justas it passes through the jugular foramen at the base of the skull. Thenodose (inferior) ganglion is a ganglion on the vagus nerve located inthe height of the transverse process of the first cervical vertebra.

Terminations of each group of fibers (SAR, RAR, and C) are found inlargely non-overlapping regions of the nucleus of the solitary tract(NTS, See FIG. 1). Second order neurons in the pathways from thesereceptors innervate neurons located in respiratory-related regions ofthe medulla, pons, and spinal cord. Those pathways control not only thebronchiole structures shown in FIG. 1, but also the rate and depth ofrespiration and cardiopulmonary activity more generally [Leszek KUBIN,George F. Alheid, Edward J. Zuperku, and Donald R. McCrimmon. Centralpathways of pulmonary and lower airway vagal afferents. J Appl Physiol101 (2006): 618-627; Jeffrey C. SMITH, Ana P. L. Abdala, Ilya A. Rybakand Julian F. R. Paton. Structural and functional architecture ofrespiratory networks in the mammalian brainstem. Phil. Trans. R. Soc. B364(2009): 2577-2587].

Both afferent and efferent parasympathetic fibers traverse or skirt thenodose and jugular ganglia (See FIG. 1). With regard to the efferentparasympathetic fibers 165, which send control signals back to thebronchioles, preganglionic motor fibers (ganglionic branches) from thedorsal motor nucleus of the vagus and the special visceral efferentsfrom the nucleus ambiguus descend to the nodose (inferior) vagalganglion and form a band that skirts the ganglion. Thus, signals thatare processed in the nucleus of the solitary tract (NTS) are sent toairway-related vagal preganglionic neurons (AVPNs), located in the mostrostral parts of the dorsal vagal nucleus and in the rostral nucleusambiguus. From these preganglionic neurons, cholinergic outflow is sentvia descending efferent intramural parasympathetic ganglia and then totracheobronchial effector systems. In particular, postganglionicefferent cholinergic fibers profusely innervate the smooth muscle 140and the submucosal glands 110. In humans, there is comparatively littleinnervation of the airway epithelium 105, airway blood vessels 145, orlamina propria 120. Because the lamina propria is poorly innervated byefferent parasympathetic nerves in humans, cells of inflammatory andimmune systems that are contained therein, such as macrophages, mayreceive little direct control there from those efferent nerves, althoughsuch control may be more significant in non-human species [CZURA C J,Tracey K J. Autonomic neural regulation of immunity. J Intern Med 257(2,2005):156-66].

The acetylcholine that is released from the preganglionic andpostganglionic nerve fibers acts on target cell membranes throughmuscarinic receptors, including M2 and M3. The M3 receptors are found onbronchial airway smooth muscle 140 and submucosal glands 110, causingsmooth muscle contraction and secretion, when activated. Thus,contraction of airway smooth muscle is mediated by acetylcholine-inducedactivation of M3 receptors, which couple to the heterotrimeric G proteinGq/11, resulting in stimulation of phospholipase C and an increase inintracellular calcium. M3 receptors are also possibly found onendothelial cells 105 and vascular smooth muscle 145. M2 receptors arealso found on airway smooth muscle and submucosal glands. However, M2activation by acetylcholine does not cause smooth muscle contraction,but instead antagonizes smooth muscle relaxation that is induced bybeta-adrenoceptors (see below). Thus, activation of M2 receptorsinhibits the generation and accumulation of cyclic adenosinemonophosphate (cAMP), thereby preventing bronchodilation. Othermechanisms may also modulate the contraction of the smooth muscle cells.For example, histamine that is released from activated mast cells mayalso cause bronchoconstriction. This is because H1-receptors are locatedin human bronchial muscle and are linked to transduction systems thatcause increased intracellular Ca2+, which leads to muscle contraction.

The M2 receptors also play a significant role in the endings of thenerve fibers that transmit acetylcholine across the neuromuscularjunction. M2 receptors in those fibers self-limit the transmission ofacetylcholine, i.e., some of the transmitted acetylcholine activatesthose M2 receptors so as to then inhibit that same transmission. Whenthis feedback inhibition becomes dysfunctional, excessive acetylcholineis transmitted to the smooth muscle, leading to hyper-responsiveness toallergens and excessive bronchoconstriction. Allergen-induced M2receptor dysfunction is dependent upon selective recruitment ofeosinophils to the airway nerves. Activated eosinophils release majorbasic protein, which binds to M2 receptors and prevents binding ofacetylcholine. The binding of a virus may also affect the structure ofthe M2

receptor itself, or viruses may act via activation of inflammatorycells, in particular

macrophages and T lymphocytes, leading to similar changes in receptorfunction that bring about similar dysfunction [FRYER A D and Jacoby D B.Muscarinic receptors and control of airway smooth muscle. Am J RespirCrit Care Med 158(5, Pt 3, 1998):5154-60; BELMONTE K E. Cholinergicpathways in the lungs and anticholinergic therapy for chronicobstructive pulmonary disease. Proc Am Thorac Soc 2(4, 2005):297-304].

Noncholinergic parasympathetic nerves also innervate the airways.Noncholinergic parasympathetic transmitters are not co-released withacetylcholine from a single population of postganglionic parasympatheticnerves. Instead, an anatomically and functionally distinctparasympathetic pathway regulates nonadrenergic, noncholinergicrelaxations of airway smooth muscle. The preganglionic nervesinnervating airway noncholinergic, parasympathetic ganglia may beunmyelinated and may originate from a distinct location in nucleusambiguus or may be derived from the dorsal motor nuclei of the vagusnerves (See FIG. 1). Unlike cholinergic contractions of the airwaysmooth muscle, which can reach a near maximum within about 30 secondsand can nearly completely reverse at the same rate, noncholinergicparasympathetic nerve-mediated relaxations are both slow in onset andreversal, requiring several minutes to reach equilibrium.

Noncholinergic parasympathetic neurotransmitters include the vasoactiveintestinal peptide (VIP), the peptide pituitary adenylatecyclase-activating peptide (PACAP), peptide histidine-isoleucine,peptide histidine-methionine, and nitric oxide (NO). Fibers with thoseneurotramsmitters are primarily under parasympathetic control, althoughsympathetic nerves in the airways have also been shown to include suchfibers [MATSUMOTO K, Aizawa H, Takata S, Inoue H, Takahashi N, Hara N.Nitric oxide derived from sympathetic nerves regulates airwayresponsiveness to histamine in guinea pigs. J Appl Physiol 83(5,1997):1432-1437]. Both VIP and NO synthase have been localized to nervefibers innervating airway smooth muscle and to parasympathetic gangliain the airways. Because such non-adrenergic, non-cholinergic nervefibers inhibit activities such as smooth muscle contraction, they areknown as iNANC fibers. Excitatory non-adrenergic, non-cholinergic(eNANC) nerve fibers also exist. Responses to those fibers are mediatedby the release of tachykinins such as substance P. In the presence ofmuscarinic blockade, vagal stimulation causes dilatation ofpreconstricted airways via noncholinergic neurotransmitters,demonstrating the dominance or overabundance of iNANC fibers relative toeNANC fibers.

It should be noted that a number of nonbronchiolar afferent nervesubtypes may also induce a withdrawal of cholinergic tone, includingbaroreceptors, skeletal muscle and diaphragmatic afferents, andpulmonary stretch receptors, some of which are also conveyed by thevagus nerve. These disparate afferent inputs may be simultaneouslyrecruited, for example, during exercise. It should also be noted thatalthough FIG. 1 shows a reflex loop involving afferent and efferentnerve fibers sending signals from and to a single bronchiole, in realitysignals from the afferent fibers emanating from one bronchiole mayresult in efferent signals that are sent to another bronchiole. This isparticularly important as it relates to the cooperative behavior ofsmooth muscle throughout the airways, as described later in connectionwith avalanches of bronchoconstriction and bronchodilation.

Turning now to control of the airways by the sympathetic nervous system,it is known that some sympathetic pulmonary afferent nerves exist.However, unlike the well-characterized parasympathetic afferent nervefibers described above, the sympathetic afferent fibers have beendescribed only as capsaicin-sensitive, substance P-containing spinalafferent neurons in the upper thoracic (T1-T4) dorsal root ganglia (DRG)that innervate the airways and lung [KOSTREVA D R, Zuperku E J, Hess GL, Coon R L, Kampine J P. Pulmonary afferent activity recorded fromsympathetic nerves. J Appl Physiol 39(1, 1975):37-40; Eun Joo O H,Stuart B. Mazzone, Brendan J. Canning and Daniel Weinreich. Reflexregulation of airway sympathetic nerves in guinea-pigs. J Physiol 573(2, 2006): 549-564].

With regard to the efferent sympathetic nerves, human airway smoothmuscle is largely devoid of sympathetic adrenergic efferent innervation(in contrast to some other mammals), with relatively few fibers reachingthe level of secondary bronchi and terminal bronchioles. Nevertheless,some sympathetic fibers do innervate the glands, vasculature, andparasympathetic ganglia of the human bronchial tree. Furthermore, recentevidence has suggested asthma patients do have such sympatheticinnervations within the bronchial smooth muscle. Alpha-adrenergicreceptors are localized on pulmonary and bronchial blood vessels,bronchial epithelial cells, submucosal glands, in parasympatheticganglia, and on cholinergic and C afferent nerve fibers, where limitedsympathetic innervation may occur. Beta-adrenergic receptors arenumerous on airway smooth muscle, despite a lack of significantsympathetic innervation there, the significance of which is thatbeta-adrenergic control may be via circulating catecholamines ratherthan by the release of neurotransmitters from local nerve fibers.

In fact, the most significant parts of the sympathetic nervous system inregards to control of the airways may be within the parasympatheticganglia and in the adrenal medulla. Postganglionic sympathetic nervefibers intermingle with cholinergic nerves in parasympathetic ganglia,where sympathetic fibers may modulate cholinergic neurotransmission[Allen C MYERS. Transmission in autonomic ganglia. RespirationPhysiology 125(1-2, 2001): 99-111;

BAKER, D. G., Basbaum, C. B., Herbert, D. A., Mitchell, R. A.Transmission in airway ganglia of ferrets: Inhibition by norepinephrine.Neurosci. Lett. 41(1983):139-43; Richardson J and Beland J.Nonadrenergic inhibitory nervous system in human airways. J Appl Physiol41: 764-771, 1976]. FIG. 1 shows fibers emanating from sympatheticganglia that impinge upon the parasympathetic ganglia. Some of thosefibers may terminate in the parasympathetic ganglia to modulate theparasympathetic fibers that reach the bronchi, and a small number of thesympathetic fibers may actually pass through or near the parasympatheticganglia to reach the bronchi.

Epinephrine acts as a circulating hormone to participate in theregulation of bronchomotor tone through the stimulation of beta-2receptors. Beta-adrenergic receptors are numerous on airway smoothmuscle, and their stimulation by circulating catecholamines producesbronchodilatation. Epinephrine is derived mostly from the adrenalmedulla, which is under the control of the sympathetic nervous system(See FIG. 1). The cells of the adrenal medulla are innervated directlyby fibers from intermediolateral nucleus (IML, in the thoracic spinalcord from T5-T11). Because it is innervated by preganglionic nervefibers, the adrenal medulla can be considered to be a specializedsympathetic ganglion. It is ordinarily only during strenuous exercisethat epinephrine concentrations are raised sufficiently to causesignificant bronchodilation, e.g., to counteract bronchospasm that isinduced by exercise in asthma [BERKIN K E, Inglis G C, Ball S G, et al.Airway responses to low concentrations of adrenaline and noradrenalinein normal subjects. Q J Exp Physiol 70(1985):203-209; Neil C THOMSON,Kenneth D Dagg, Scott G Ramsay. Humoral control of airway tone. Thorax51(1996):461-464]. Repeated stimulation of some vagus nerve fibers maycause the repeated pulsatile systemic release of epinephrine (and/orother catecholamies), leading eventually to circulating steady stateconcentrations of catecholamines that are determined by the stimulationfrequency as well as the half-life of circulating catecholamines.

The preceding paragraphs describe the efferent and afferent nerve fibersthat respectively send signals to and from the bronchi and bronchioles.The paragraphs that follow describe the processing of the afferentsensory signals within the central nervous system to produce theefferent controlling signals (see FIG. 1). The neurons of this centralrespiratory network drive two functionally and anatomically distinctpools of motoneurons. Both groups have to be precisely coordinated toensure efficient ventilation. One set, located within the spinal cord,innervates the diaphragm and intercostal muscles that force air into thelungs. A second group of motoneurons, with which this discussion isprimarily concerned, is located within the nucleus ambiguus and to alesser extent within the dorsal motor nucleus of the vagus. The lattergroup projects via the vagus nerve to coordinate the activity oflaryngeal and bronchial muscle so as to control airway resistance andairflow.

The relevant interconnected centers shown in FIG. 1 are located in themedulla (nucleus tractus solitarius, nucleus ambiguus and dorsal motornucleus of the vagus, rostral ventral lateral medulla, rostral ventralmedial medulla, medullary raphe nuclei), the pons/midbrain(periaqueducatal gray, locus ceruleus, raphe nuclei—e.g. dorsal), thediencephalon (hypothalamic nuclei, particularly the paraventricularnucleus of the hypothalamus), and the telencephalon (amygdala and itsconnections to the brain cortex). These same centers are involved moregenerally in the integration of cardiopulmonary functions and theregulation of body fluids (e.g., baroreflex and pH or CO2 chemoreceptionreflexes) [David JORDAN. Central nervous pathways and control of theairways. Respiration Physiology 125(2001): 67-81; Leszek KUBIN, GeorgeF. Alheid, Edward J. Zuperku, and Donald R. McCrimmon. Central pathwaysof pulmonary and lower airway vagal afferents. J Appl Physiol 101(2006):618-627; Musa A. HAXHIU, Prabha Kc, Constance T. Moore, Sandra S.Acquah, Christopher G. Wilson, Syed I. Zaidi, V. John Massari, andDonald G. Ferguson. Brain stem excitatory and inhibitory signalingpathways regulating bronchoconstrictive responses. J Appl Physiol98(2005): 1961-1982; KC P, Martin R J. Role of central neurotransmissionand chemoreception on airway control. Respir Physiol Neurobiol 173(3,2010):213-22; Bradley J. UNDEM and Carl Potenzieri. Autonomic NeuralControl of Intrathoracic Airways. Comprehensive Physiology2(2012):1241-1267; R. A. L. DAMPNEY. Functional organization of centralpathways regulating the cardiovascular system. Physiological Reviews74:323-364].

Consider first the input to the central pathways. Vagal afferentstraverse the brainstem in the solitary tract, with some eighty percentof the terminating synapses being located in the nucleus of the tractussolitarius (NTS). The NTS projects to a wide variety of structures, asshown in FIG. 1, including the amygdala, raphe nuclei, periaqueductalgray, nucleus ambiguus and the hypothalamus. The NTS also projects tothe parabrachial nucleus, which in turn projects to the hypothalamus,the thalamus, the amygdala, the anterior insular, and infralimbiccortex, lateral prefrontal cortex, and other cortical regions. [JEAN A.The nucleus tractus solitarius: neuroanatomic, neurochemical andfunctional aspects. Arch Int Physiol Biochim Biophys 99(5,1991):A3-A52].

A subset of NTS neurons receiving afferent input from SARs (termed pumpor P-cells) mediates the Breuer-Hering reflexes and inhibits neuronsreceiving afferent input from RARs. Those reflexes are related to thecontrol of spontaneous breathing rate and depth, especially in childrenand exercising adults, and they are also related to respiratory sinusarrhythmia, in which the heart rate is modulated by the respiratory rateand depth.

P-cells and second order neurons in the RAR pathway provide inputs toregions of the ventrolateral medulla involved in control of respiratorymotor pattern. The core circuit components that constitute the neuralmachinery for generating respiratory rhythm and shaping inspiratory andexpiratory motor patterns are distributed among three adjacentstructural compartments in the ventrolateral medulla: the Botzingercomplex, pre-Botzinger complex and rostral ventral respiratory group.

Axon collaterals from both P-cells and RAR interneurons, and likely fromNTS interneurons in the C-fiber pathway, project to the para brachialpontine region where they may contribute to plasticity in respiratorycontrol, as well as integration of respiratory control with othersystems, including those that provide for voluntary control ofbreathing, sleep-wake behavior, and emotions.

Consider now the output from the central pathways. Airway-related vagalpreganglionic neurons (AVPNs) are the final common pathway from thecentral nervous system to the airways and transmit signals to theintrinsic bronchial ganglia that are part of the network for automaticfeedback control. In most mammals, the motor preganglionic component ofthe network innervating the airways arises mainly from the nucleusambiguus and to a lesser extent from the dorsal motor nucleus of thevagus (DMV). Of these two groups of neurons, AVPNs within the rostralnucleus ambiguus play a greater role in generating cholinergic outflowto airway smooth muscle.

Acetylcholine release at the bronchial smooth muscle is triggered by theactivation of AVPNs, resulting in bronchoconstriction. Such activationof AVPNs is typically triggered by vagal C fibers via the activation ofthe NTS, wherein glutamate is released into the AVPNs. This C fiberactivation may be in response to irritants, allergens, trauma, oridiopathic mechanisms associated with hypersensitivity. The activationmay also be via A-delta fibers whose cell bodies reside in the jugularganglia, which (like the C fibers) resemble the nociceptive fibers ofthe somatosensory system in that they have relatively high thresholds tomechanical stimuli and respond to classic nociceptive fiber-selectivestimuli such as capsaicin and bradykinin [Michael J. CARR and Bradley J.Undem. Bronchopulmonary afferent nerves. Respirology 8(2003):291-301].

Thus, the simplest feedback loop shown in FIG. 1 is one in which signalsfrom afferent fibers to the NTS result in subsequent direct activationof the AVPNs by the NTS, resulting in a level of broncho-constrictionthat is a function of the magnitude of the C or jugular A-delta fiberactivation. It is understood that this level of constriction is largelya balance between the effects of cholinergic stimulation, iNANCrelaxation, and relaxation due to circulating catecholamines.Mechanistically, the preganglionic nerves innervating airwaynoncholinergic, parasympathetic ganglia may originate from a distinctlocation in nucleus ambiguus or may be derived from the dorsal motornuclei of the vagus nerves (dmnX).

However, AVPNs receive connections from multiple sites within the brain,not just the NTS, and these additional connections may inhibitglutamate-mediated activation of the AVPNs. Such additional connectionshave been demonstrated by retrograde transneuronal labeling withpseudorabies virus in C8 cord-transected rats. They include connectionsof the AVPNs to the amygdala, hypothalamus, periaqueductal grey matterof the midbrain (PAG), locus ceruleus, and raphe nuclei (see FIG. 1)[HADZIEFENDIC S, Haxhiu M A. CNS innervation of vagal preganglionicneurons controlling peripheral airways: a transneuronal labeling studyusing pseudorabies virus. J Auton Nervous Syst. 76(2-3, 1999):135-145;HAXHIU M A, Jansen A S P, Cherniack N S, Loewy A D. CNS innervation ofairway-related parasympathetic preganglionic neurons: a transneuronallabeling study using pseudorabies virus. Brain Res 618(1,1993):115-134].

Thus, the response of the AVPNs to excitatory inputs also depends on theinhibitory inflow to the AVPNs. Many inhibitory cell groups projectingto the AVPNs are linked to the hypothalamus, and a function of thoseprojections is related in part to the control of respiration duringsleep, maintenance of attention, motivation, and arousal states [Musa A.HAXHIU, Serdia O. Mack, Christopher G. Wilson, Pingfu Feng, and KingmanP. Strohl. Sleep networks and the anatomic and physiologic connectionswith respiratory control. Frontiers in Bioscience 8(2003): d946-962].When activated, GABA- and galaninergic cells inhibithistamine-containing neurons of the tuberomamillary nucleus (TMN) andthe orexin-producing cells of the lateral hypothalamic area (LHA). Thisinhibition causes withdrawal of excitatory inputs from TMN and LHAneurons to serotonin (5-HT) expressing cells of raphe nuclei (RN) andthe locus coeruleus (LC) norepinephrine-synthesizing cells. In addition,activation of neurons within the ventrolateral preoptic area directlyinhibits LC and RN neurons, as well as GABA-containing cells of theventrolateral periaqueductal gray (PAG), which project to AVPNs.Stimulation of the LC noradrenergic cell group and activation ofparabrachial nucleus is known induce centrally mediated airway smoothmuscle relaxation [Michele BAROFFIO, Giovanni Barisione, Emanuele Crimiand Vito Brusasco. Noninflammatory mechanisms of airwayhyper-responsiveness in bronchial asthma: an overview. Ther Adv RespirDis 3(4, 2009): 163-174; Musa A. HAXHIU, Bryan K. Yamamoto, Ismail A.Dreshaj and Donald G. Ferguson. Activation of the midbrainperiaqueductal gray induces airway smooth muscle relaxation. J ApplPhysiol 93(2002):440-449; HAXHIU, Musa A., Prabha Kc, Burim Neziri,Bryan K. Yamamoto, Donald G. Ferguson, and V. John Massari.Catecholaminergic microcircuitry controlling the output ofairway-related vagal preganglionic neurons. J Appl Physiol 94(2003):1999-2009]. Such inhibitory mechanisms may be dysfunctional in patientswith airway disease such as asthma [Christopher G. WILSON, ShamimaAkhter, Catherine A. Mayer, Prabha Kc, Kannan V. Balan, Paul Ernsberger,and Musa A. Haxhiu. Allergic lung inflammation affects centralnoradrenergic control of cholinergic outflow to the airways in ferrets.J Appl Physiol 103(2007): 2095-2104].

Thus, acting in opposition to glutamate-mediated (and possibly substanceP) activation of the AVPNs by the NTS are GABA, and/or serotonin, and/ornorepinephrine from the periaqueductal gray, raphe nuclei, and locuscoeruleus, respectively. As shown in FIG. 1, control of the inhibitoryinfluence by the PAC, LC, and RN on the AVPNs may be exerted directly atsites within the nucleus ambiguus or dorsal motor nucleus. Theinhibitory influence may also be on the nucleus tractus solitarius(NTS), which is connected bidirectionally to these centers. Thus, theinhibition may decrease the activation of the AVPNs by the NTS ratherthan simply inhibiting an already-existing activation of the AVPNs bythe NTS. Alternatively, the inhibitory influence on the NTS may occurindirectly via the hypothalamus owing to bidirectional connectionsbetween the NTS and hypothalamus.

The activation of inhibitory circuits in the periaqueductal gray, raphenucei, and locus coeruleus by the hypothalamus or NTS may also causecircuits connecting each of these structures to modulate one another.Thus, the periaqueductal gray communicates with the raphe nuclei andwith the locus coeruleus, and the locus coeruleus communicates with theraphe nuclei, as shown in FIG. 1 [PUDOVKINA O L, Cremers T I, WesterinkB H. The interaction between the locus coeruleus and dorsal raphenucleus studied with dual-probe microdialysis. Eur J Pharmacol 7(2002);445(1-2):37-42; REICHLING D B, Basbaum A I. Collateralization ofperiaqueductal gray neurons to forebrain or diencephalon and to themedullary nucleus raphe magnus in the rat. Neuroscience 42(1,1991):183-200; BEHBEHANI M M. The role of acetylcholine in the functionof the nucleus raphe magnus and in the interaction of this nucleus withthe periaqueductal gray. Brain Res 252(2, 1982):299-307; de Souza MORENOV, Bícego K C, Szawka R E, Anselmo-Franci J A, Gargaglioni L H.Serotonergic mechanisms on breathing modulation in the rat locuscoeruleus. Pflugers Arch 459(3, 2010):357-68].

Another structure also has a significant influence on AVPN activity,namely, the amygdala. The prefrontal cortex innervates the amygdala,which projects to multiple targets regulating autonomic functions,including the PAG, the NTS, and the nucleus ambiguus. Projections fromthe amygdala to the PAG are significant because the PAG neuronscoordinate functions of multiple visceral organs involved in responsesto stress, including those involving the airway. The effects of amygdalaactivity transmitted via the PAG to the AVPNs may be inhibitory orstimulatory, depending upon whether the patient is experiencing activeor passive coping responses. As shown in FIG. 1, such control of AVPNactivity via the amygdala may be modulated by connections to the NTS,either directly or via the hypothalamus.

Finally, consider central modulation of the airways via the sympatheticnervous system. Only a limited number of discrete regions within thesupraspinal central nervous system project to sympathetic preganglionicneurons in the intermediolateral column (see FIG. 1). The most importantof these regions are the rostral ventral lateral medulla (RVLM), therostral ventromedial medulla (RVMM), the midline raphe, theparaventricular nucleus (PVN) of the hypothalamus, the medullocervicalcaudal pressor area (mCPA), and the A5 cell group of the pons. The firstfour of these connections to the intermediolateral nucleus are shown inFIG. 1 [STRACK A M, Sawyer W B, Hughes J H, Platt K B, Loewy A D. Ageneral pattern of CNS innervation of the sympathetic outflowdemonstrated by transneuronal pseudorabies viral infections. Brain Res.491(1, 1989): 156-162].

The rostral ventral lateral medulla (RVLM) is the primary regulator ofthe sympathetic nervous system, sending excitatory fibers(glutamatergic) to the sympathetic preganglionic neurons located in theintermediolateral nucleus of the spinal cord. Afferents affectingcardiopulmonary function synapse in the NTS, and their projections reachthe RVLM via the caudal ventrolateral medulla. However, restingsympathetic tone also comes from sources above the pons, fromhypothalamic nuclei, various hindbrain and midbrain structures, as wellas the forebrain and cerebellum, which synapse in the RVLM. Only thehypothalamic projection to the RVLM is shown in FIG. 1 [KC P, Dick T E.Modulation of cardiorespiratory function mediated by the paraventricularnucleus. Respir Physiol Neurobiol 174(1-2, 2010): 55-64].

The RVLM shares its role as a primary regulator of the sympatheticnervous system with the rostral ventromedial medulla (RVMM) andmedullary raphe. Differences in function between the RVLM versusRVMM/medullary raphe have been elucidated in the case of cardiovascularcontrol. In that case, barosensitive sympathetic efferents appear to beregulated primarily through the RVLM, whereas the cutaneous circulationis regulated predominantly through the RVMM and medullary raphe. In thecase of respiratory control, less is known, although it is thought thatnociceptive sympathetic efferents are regulated through the RVMM andserotonin-containing medullary raphe. Differential control of the RVLMby the hypothalamus may also occur via circulating hormones such asvasopressin. The RVMM contains at least three populations of nitricoxide synthase neurons that send axons to innervate functionally similarsites in the NTS and nucleus ambiguus. Circuits connecting the RVMM andRVLM may be secondary, via the NTS and hypothalamus [Paul M. PILOWSKY,Mandy S. Y. Lung, Darko Spirovski and Simon McMullan. Differentialregulation of the central neural cardiorespiratory system bymetabotropic neurotransmitters. Phil. Trans. R. Soc. B 364(2009):2537-2552].

FIG. 1 shows the afferent and efferent limbs of neural control to asingle bronchiole, in which afferent signals from a bronchiole result inefferent controlling signals to that same bronchiole. The figure doesnot show how afferent signals originating from one bronchiole generateefferent signals to other bronchioles, which may be at the same ordifferent levels of bronchial bifurcation. If the smooth muscle in allbronchia and bronchioles were to constrict and dilate in unison, thenthe depiction in FIG. 1 would reflect the circuitry of the lung as awhole. However, individual normal bronchioles actually undergo constantconstriction and dilation, such that the diameters of their lumens mayvary considerably over the course of even a few minutes. Normally, somebronchioles are constricting while others are dilating, but thetime-varying heterogeneity of airway caliber throughout the lung isnormally sufficient to bring air to all the alveoli, because anyconstricted bronchiole would reopen in a relatively short period oftime. This oscillation of constriction and dilation of individualbronchioles throughout the lung leads to physiological fluctuations inairway resistance at the level of the whole lung [QUE C L, Kenyon C M,Olivenstein R, Macklem P T, Maksym G N. Homeokinesis and short-termvariability of human airway caliber. J Appl Physiol 91(3, 2001):1131-41;MUSKULUS M, Slats A M, Sterk P J, Verduyn-Lunel S. Fluctuations anddeterminism of respiratory impedance in asthma and chronic obstructivepulmonary disease. J Appl Physiol 109(6, 2010):1582-91; FREY U, MaksymG, Suki B. Temporal complexity in clinical manifestations of lungdisease. J Appl Physiol 110(6, 2011):1723-31].

Accordingly, the present invention considers bronchiole segments to beoscillators, in which a mathematical variable corresponding to eachbronchiole segment represents the time-varying radius of a bronchiolelumen, relative to a value representing a time-averaged radius of thatbronchiole. Because segments of the bronchial tree are fluctuatingaccording to the invention, the oscillating branches collectively giverise to fluctuations in overall respiratory impedance. It is thoughtthat an asthma attack (or other bronchoconstrictive exacerbation) maycorrespond to an avalanche of airway constrictions, in which theconstriction in one bronchiole segment increases the likelihood thatanother bronchiole branch in the same tree structure of the lung willconstrict. The mechanisms linking one bronchiole segment to anotherinclude: the shared airflow in the lumens that connect one bronchiole toanother; and neural connections to multiple bronchioles. As a result ofthe interconnected bronchiole fluctuations, some initial heterogeneityof airway constriction within different regions of the lung, which mightseem to be of little physiological consequence, may actually becomeamplified by avalanches of airway constrictions, such that eventuallylarge heterogeneous regions of the lung become unavailable for normalrespiration.

Models have been constructed to explain such heterogeneity andavalanches (of closure and of reopening), but they have been used onlyto assess the risk of an asthma attack, rather than to explain orpredict the actual occurrence of an asthma attack. A model of lungdynamics that is disclosed towards the end of this application isintended to make such a prediction for use in a feedforward controller.It does so by making oscillation of any one bronchiole oscillator be afunction of the state of other bronchiole oscillators, as well as afunction of external conditions such as the presence of inhaledirritants and the accumulated effects of electrical stimulation of avagus nerve. In one aspect of the present invention, the stimulation ofa vagus nerve randomizes (e.g., through the quasi-random stimulation ofindividual fibers within the vagus nerve) afferent neural signals sentto the central nervous system, thereby resetting the phase relationsbetween bronchiole oscillators, and consequently allowing for anavalanche-type reopening of bronchioles within regions of the lung thathad been poorly ventilated, or for an inhibition of an avalanche-typebronchiolar closing. Quasi-random stimulation of efferent fibers by VNSmay also be involved in such avalanche-type reopening [ALENCAR A M,Arold S P, Buldyrev S V, Majumdar A, Stamenovic D, Stanley H E, Suki B.Physiology: Dynamic instabilities in the inflating lung. Nature417(6891, 2002):809-11; SUKI B, Frey U. Temporal dynamics of recurrentairway symptoms and cellular random walk. J Appl Physiol 95(5,2003):2122-7; VENEGAS J G, Winkler T, Musch G, Vidal Melo M F, LayfieldD, Tgavalekos N, Fischman A J, Callahan R J, Bellani G, Harris R S.Self-organized patchiness in asthma as a prelude to catastrophic shifts.Nature 434(7034, 2005):777-82; FREY U, Brodbeck T, Majumdar A, Taylor DR, Town G I, Silverman M, Suki B. Risk of severe asthma episodespredicted from fluctuation analysis of airway function. Nature 438(7068,2005):667-70; FREY U. Predicting asthma control and exacerbations:chronic asthma as a complex dynamic model. Curr Opin Allergy ClinImmunol 7(3, 2007):223-30; MULLALLY W, Betke M, Albert M, Lutchen K.Explaining clustered ventilation defects via a minimal number of airwayclosure locations. Ann Biomed Eng 37(2, 2009):286-300; POLITI A Z,Donovan G M, Tawhai M H, Sanderson M J, Lauzon A M, Bates J H, Sneyd J.A multiscale, spatially distributed model of asthmatic airwayhyper-responsiveness. J Theor Biol 266(4, 2010):614-24; TAWHAI M H,Bates J H. Multi-scale lung modeling. J Appl Physiol 110(5,2011):1466-72; SUKI B, Bates J H. Emergent behavior in lung structureand function. J Appl Physiol 110(4, 2011):1109-10; KACZKA D W, Lutchen KR, Hantos Z. Emergent behavior of regional heterogeneity in the lung andits effects on respiratory impedance. J Appl Physiol 110(5,2011):1473-81].

FIG. 1 also shows a vagus nerve being electrically stimulated accordingto the present invention, which in general would modulate the activityof both afferent and efferent vagal nerve fibers. The particularstructures within the patient that will be affected by the stimulationdepend upon the details of the stimulation protocol. As described below,depending on whether the stimulation voltage is high or low, thestimulation may either constrict or dilate bronchial smooth muscle. Astaught below in this disclosure, particular electrical stimulationwaveforms bring about the dilation of constricted bronchi andbronchioles and also produce a minimum of unwanted side effects. Theabsence or minimization of unwanted side effects is also made possibleby the use of noninvasive electrical stimulation devices that aredisclosed herein, which shape the electrical stimulation in such a wayas avoid the stimulation of tissue near the vagus nerve that would causepain, unwanted muscle twitching, or other unwanted non-selectiveeffects. Thus, the method of vagal nerve stimulation that is disclosedbelow uses parameters (intensity, pulse-width, frequency, duty cycle,etc.) that selectively activate certain structures shown in FIG. 1. Thestimulation waveform parameters are different from those used to treatother diseases with vagus nerve stimulation, such as epilepsy [Jeong-HoCHAE, Ziad Nahas, Mikhail Lomarev, Stewart Denslow, Jeffrey P.Lorberbaum, Daryl E. Bohning, Mark S. George. A review of functionalneuroimaging studies of vagus nerve stimulation (VNS). Journal ofPsychiatric Research 37 (2003) 443-455; G. C. Albert, C. M. Cook, F. S.Prato, A. W. Thomas. Deep brain stimulation, vagal nerve stimulation andtranscranial stimulation: An overview of stimulation parameters andneurotransmitter release. Neuroscience and Biobehavioral Reviews 33(2009): 1042-1060].

Mention was made above of a phase-resetting mechanism, whereinstimulation of the vagus nerve blocks a bronchial-closing avalanche orpromotes a re-opening bronchial avalanche. In view of the foregoingdiscussion of ways in which the vagus nerve can affect the bronchi, alarge number of additional physiological mechanisms can be envisaged,many of which are not mutually exclusive. Depending on the details ofthe stimulation waveform and stimulation devices, the vagal nervestimulation may stimulate, block, or otherwise modulate particular typesof nerve fibers within the vagus nerve (e.g., afferent vs. efferent,nerve fiber types A, B, and/or C, parasympathetic or sympathetic, etc.).The stimulation may generate action potentials that propagate inorthodromal or in antidromal directions. More particular mechanisms mayalso be envisaged. For example, parasympathetic efferent cholinergicfibers could be blocked directly, thereby inhibitingbronchoconstriction. Such inhibition could involve muscarinic receptorsM2 or M3 or both. As another example, the VNS could result in thestimulation of efferent iNANC nerve fibers that promote bronchodilation.Alternatively, small numbers of sympathetic efferent fibers coulddirectly cause relaxation of bronchial smooth muscle, or fibers fromsympathetic ganglia could stimulate parasympathetic ganglia, therebyindirectly stimulating iNANC fibers to cause relaxation of bronchialsmooth muscle. Alternatively, fibers from sympathetic ganglia couldinhibit parasympathetic ganglia, thereby inhibiting parasympatheticcholinergic fibers from constricting smooth muscle. Alternatively,norepinephrine outflow from the sympathetic-innervated pulmonaryvasculature could promote bronchodilation, or fibers from theinteromediolateral nucleus could stimulate the adrenal gland, producingcirculating epinephrine that relaxes bronchial smooth muscle.Furthermore, stimulation of the vagus nerve could directly inhibit theactivation of the AVPNs by the nucleus tractus solitarius (NTS).Alternatively, the inhibitory influence on the NTS may occur indirectlyvia activation of the hypothalamus, and/or amygdala and/orperiaqueductal gray and/or locus coeruleus and/or raphe nuclei.Alternatively, the inhibition may be the combined result of inhibitoryand excitatory influences within the AVPNs (the + and − influences shownin FIG. 1). According to this aspect of the invention, noninvasive VNSwith the disclosed devices activates pathways causing release ofnorepinephrine, serotonin and/or GABA (inhibitory neurotransmitters)onto the AVPNs, thereby preventing or reducing the release ofacetylcholine in the airways and resulting in bronchorelaxation.According to this view, noninvasive VNS acts as a central, specific,airway anticholinergic, but without any of the side effects of systemicanticholinergic therapy. In addition, these same inhibitoryneurotransmitters act on the mucous glands throughout the airwaypassages in the nose, mouth, throat and lungs of the patient. Therefore,the noninvasive VNS taught by the present invention also serves toinhibit mucous production in these airway passages, resulting inincreased airflow throughout these passages. Thus, the present inventioncan provide a dual benefit: (1) an immediate reduction in acetylcholinerelease to the lungs, providing an immediate (within minutes or seconds)bronchodilation effect for the patient; and (2) a decrease in mucousproduction which provides a more gradual improvement of airflow to thepatient. After providing a description of Applicant's nerve stimulatingdevices and methods, the present disclosure will describe animalexperiments that test some of these potential mechanisms.

Description of Applicant's Magnetic and Electrode-Based NerveStimulating/Modulating Devices, Describing in Particular the ElectricalWaveform that is Used to Stimulate a Vagus Nerve.

FIG. 2A is a schematic diagram of Applicant's magnetic nervestimulating/modulating device 301 for delivering impulses of energy tonerves for the treatment of medical conditions, particularly treatmentof broncho-constriction. As shown, device 301 may include an impulsegenerator 310; a power source 320 coupled to the impulse generator 310;a control unit 330 in communication with the impulse generator 310 andcoupled to the power source 320; and a magnetic stimulator coil 341coupled via wires to impulse generator coil 310. The stimulator coil 341is toroidal in shape, due to its winding around a toroid of corematerial.

Although the magnetic stimulator coil 341 is shown in FIG. 2A to be asingle coil, in practice the coil may also comprise two or more distinctcoils, each of which is connected in series or in parallel to theimpulse generator 310. Thus, the coil 341 that is shown in FIG. 2Arepresents all the magnetic stimulator coils of the device collectively.In a preferred embodiment that is discussed below, coil 341 actuallycontains two coils that may be connected either in series or in parallelto the impulse generator 310.

The item labeled in FIG. 2A as 351 is a volume, surrounding the coil341, that is filled with electrically conducting medium. As shown, themedium not only encloses the magnetic stimulator coil, but is alsodeformable such that it is form-fitting when applied to the surface ofthe body. Thus, the sinuousness or curvature shown at the outer surfaceof the electrically conducting medium 351 corresponds also tosinuousness or curvature on the surface of the body, against which theconducting medium 351 is applied, so as to make the medium and bodysurface contiguous. As time-varying electrical current is passed throughthe coil 341, a magnetic field is produced, but because the coil windingis toroidal, the magnetic field is spatially restricted to the interiorof the toroid. An electric field and eddy currents are also produced.The electric field extends beyond the toroidal space and into thepatient's body, causing electrical currents and stimulation within thepatient. The volume 351 is electrically connected to the patient at atarget skin surface in order to significantly reduce the current passedthrough the coil 341 that is needed to accomplish stimulation of thepatient's nerve or tissue. In a preferred embodiment of the magneticstimulator that is discussed below, the conducting medium with which thecoil 341 is in contact need not completely surround the toroid.

The design of the magnetic stimulator 301, which is also adapted hereinfor use with surface electrodes, makes it possible to shape the electricfield that is used to selectively stimulate a relatively deep nerve suchas a vagus nerve in the patient's neck. Furthermore, the design producessignificantly less pain or discomfort (if any) to a patient thanstimulator devices that are currently known in the art. Conversely, fora given amount of pain or discomfort on the part of the patient (e.g.,the threshold at which such discomfort or pain begins), the designachieves a greater depth of penetration of the stimulus under the skin.

An alternate embodiment of the present invention is shown in FIG. 2B,which is a schematic diagram of an electrode-based nervestimulating/modulating device 302 for delivering impulses of energy tonerves for the treatment of medical conditions. As shown, device 302 mayinclude an impulse generator 310; a power source 320 coupled to theimpulse generator 310; a control unit 330 in communication with theimpulse generator 310 and coupled to the power source 320; andelectrodes 340 coupled via wires 345 to impulse generator 310. In apreferred embodiment, the same impulse generator 310, power source 320,and control unit 330 may be used for either the magnetic stimulator 301or the electrode-based stimulator 302, allowing the user to changeparameter settings depending on whether coils 341 or the electrodes 340are attached.

Although a pair of electrodes 340 is shown in FIG. 2B, in practice theelectrodes may also comprise three or more distinct electrode elements,each of which is connected in series or in parallel to the impulsegenerator 310. Thus, the electrodes 340 that are shown in FIG. 2Brepresent all electrodes of the device collectively.

The item labeled in FIG. 2B as 350 is a volume, contiguous with anelectrode 340, that is filled with electrically conducting medium. Asdescribed below in connection with particular embodiments of theinvention, conducting medium in which the electrode 340 is embedded neednot completely surround an electrode. As also described below inconnection with a preferred embodiment, the volume 350 is electricallyconnected to the patient at a target skin surface in order to shape thecurrent density passed through an electrode 340 that is needed toaccomplish stimulation of the patient's nerve or tissue. The electricalconnection to the patient's skin surface is through an interface 351. Inone embodiment, the interface is made of an electrically insulating(dielectric) material, such as a thin sheet of Mylar. In that case,electrical coupling of the stimulator to the patient is capacitive. Inother embodiments, the interface comprises electrically conductingmaterial, such as the electrically conducting medium 350 itself, or anelectrically conducting or permeable membrane. In that case, electricalcoupling of the stimulator to the patient is ohmic. As shown, theinterface may be deformable such that it is form-fitting when applied tothe surface of the body. Thus, the sinuousness or curvature shown at theouter surface of the interface 351 corresponds also to sinuousness orcurvature on the surface of the body, against which the interface 351 isapplied, so as to make the interface and body surface contiguous.

The control unit 330 controls the impulse generator 310 to generate asignal for each of the device's coils or electrodes. The signals areselected to be suitable for amelioration of a particular medicalcondition, when the signals are applied non-invasively to a target nerveor tissue via the coil 341 or electrodes 340. It is noted that nervestimulating/modulating device 301 or 302 may be referred to by itsfunction as a pulse generator. Patent application publicationsUS2005/0075701 and US2005/0075702, both to SHAFER contain descriptionsof pulse generators that may be applicable to the present invention. Byway of example, a pulse generator is also commercially available, suchas Agilent 33522A Function/Arbitrary Waveform Generator, AgilentTechnologies, Inc., 5301 Stevens Creek Blvd Santa Clara Calif. 95051.

The control unit 330 may also comprise a general purpose computer,comprising one or more CPU, computer memories for the storage ofexecutable computer programs (including the system's operating system)and the storage and retrieval of data, disk storage devices,communication devices (such as serial and USB ports) for acceptingexternal signals from the system's keyboard and computer mouse as wellas any externally supplied physiological signals (see FIG. 15),analog-to-digital converters for digitizing externally supplied analogsignals (see FIG. 15), communication devices for the transmission andreceipt of data to and from external devices such as printers and modemsthat comprise part of the system, hardware for generating the display ofinformation on monitors that comprise part of the system, and busses tointerconnect the above-mentioned components. Thus, the user may operatethe system by typing instructions for the control unit 330 at a devicesuch as a keyboard and view the results on a device such as the system'scomputer monitor, or direct the results to a printer, modem, and/orstorage disk. Control of the system may be based upon feedback measuredfrom externally supplied physiological or environmental signals.Alternatively, the control unit 330 may have a compact and simplestructure, for example, wherein the user may operate the system usingonly an on/off switch and power control wheel or knob.

Parameters for the nerve or tissue stimulation include power level,frequency and train duration (or pulse number). The stimulationcharacteristics of each pulse, such as depth of penetration, strengthand selectivity, depend on the rise time and peak electrical energytransferred to the electrodes or coils, as well as the spatialdistribution of the electric field that is produced by the electrodes orcoils. The rise time and peak energy are governed by the electricalcharacteristics of the stimulator and electrodes or coils, as well as bythe anatomy of the region of current flow within the patient. In oneembodiment of the invention, pulse parameters are set in such as way asto account for the detailed anatomy surrounding the nerve that is beingstimulated [Bartosz SAWICKI, Robert Szmur

o, Przemys

aw P

onecki, Jacek Starzyński, Stanis

aw Wincenciak, Andrzej Rysz. Mathematical Modeling of Vagus NerveStimulation. pp. 92-97 in: Krawczyk, A. Electromagnetic Field, Healthand Environment: Proceedings of EHE'07. Amsterdam, 105 Press, 2008].Pulses may be monophasic, biphasic or polyphasic. Embodiments of theinvention include those that are fixed frequency, where each pulse in atrain has the same inter-stimulus interval, and those that havemodulated frequency, where the intervals between each pulse in a traincan be varied.

FIG. 2C illustrates an exemplary electrical voltage/current profile fora stimulating, blocking and/or modulating impulse applied to a portionor portions of selected nerves in accordance with an embodiment of thepresent invention. For the preferred embodiment, the voltage and currentrefer to those that are non-invasively produced within the patient bythe stimulator coils or electrodes. As shown, a suitable electricalvoltage/current profile 400 for the blocking and/or modulating impulse410 to the portion or portions of a nerve may be achieved using pulsegenerator 310. In a preferred embodiment, the pulse generator 310 may beimplemented using a power source 320 and a control unit 330 having, forinstance, a processor, a clock, a memory, etc., to produce a pulse train420 to the coil 341 or electrodes 340 that deliver the stimulating,blocking and/or modulating impulse 410 to the nerve. Nervestimulating/modulating device 301 or 302 may be externally poweredand/or recharged or may have its own power source 320. The parameters ofthe modulation signal 400, such as the frequency, amplitude, duty cycle,pulse width, pulse shape, etc., are preferably programmable. An externalcommunication device may modify the pulse generator programming toimprove treatment.

In addition, or as an alternative to the devices to implement themodulation unit for producing the electrical voltage/current profile ofthe stimulating, blocking and/or modulating impulse to the electrodes orcoils, the device disclosed in patent publication No. US2005/0216062 maybe employed. That patent publication discloses a multifunctionalelectrical stimulation (ES) system adapted to yield output signals foreffecting electromagnetic or other forms of electrical stimulation for abroad spectrum of different biological and biomedical applications,which produce an electric field pulse in order to non-invasivelystimulate nerves. The system includes an ES signal stage having aselector coupled to a plurality of different signal generators, eachproducing a signal having a distinct shape, such as a sine wave, asquare or a saw-tooth wave, or simple or complex pulse, the parametersof which are adjustable in regard to amplitude, duration, repetitionrate and other variables. Examples of the signals that may be generatedby such a system are described in a publication by LIBOFF [A. R. LIBOFF.Signal shapes in electromagnetic therapies: a primer. pp. 17-37 in:Bioelectromagnetic Medicine (Paul J. Rosch and Marko S. Markov, eds.).New York: Marcel Dekker (2004)]. The signal from the selected generatorin the ES stage is fed to at least one output stage where it isprocessed to produce a high or low voltage or current output of adesired polarity whereby the output stage is capable of yielding anelectrical stimulation signal appropriate for its intended application.Also included in the system is a measuring stage which measures anddisplays the electrical stimulation signal operating on the substancebeing treated as well as the outputs of various sensors which senseconditions prevailing in this substance whereby the user of the systemcan manually adjust it or have it automatically adjusted by feedback toprovide an electrical stimulation signal of whatever type the userwishes, who can then observe the effect of this signal on a substancebeing treated.

The stimulating, blocking and/or modulating impulse signal 410preferably has a frequency, an amplitude, a duty cycle, a pulse width, apulse shape, etc. selected to influence the therapeutic result, namely,stimulating, blocking and/or modulating some or all of the transmissionof the selected nerve. For example, the frequency may be about 1 Hz orgreater, such as between about 15 Hz to 50 Hz, more preferably around 25Hz. The modulation signal may have a pulse width selected to influencethe therapeutic result, such as about 1 microseconds to about 1000microseconds. For example, the electric field induced or produced by thedevice within tissue in the vicinity of a nerve may be about 5 to 600V/m, preferably less than 100 V/m, and even more preferably less than 30V/m. The gradient of the electric field may be greater than 2 V/m/mm.More generally, the stimulation device produces an electric field in thevicinity of the nerve that is sufficient to cause the nerve todepolarize and reach a threshold for action potential propagation, whichis approximately 8 V/m at 1000 Hz. The modulation signal may have a peakvoltage amplitude selected to influence the therapeutic result, such asabout 0.2 volts or greater, such as about 0.2 volts to about 40 volts.

An objective of the disclosed stimulators is to provide both nerve fiberselectivity and spatial selectivity. Spatial selectivity may be achievedin part through the design of the electrode or coil configuration, andnerve fiber selectivity may be achieved in part through the design ofthe stimulus waveform, but designs for the two types of selectivity areintertwined. This is because, for example, a waveform may selectivelystimulate only one of two nerves whether they lie close to one anotheror not, obviating the need to focus the stimulating signal onto only oneof the nerves [GRILL W and Mortimer J T. Stimulus waveforms forselective neural stimulation. IEEE Eng. Med. Biol. 14 (1995): 375-385].These methods complement others that are used to achieve selective nervestimulation, such as the use of local anesthetic, application ofpressure, inducement of ischemia, cooling, use of ultrasound, gradedincreases in stimulus intensity, exploiting the absolute refractoryperiod of axons, and the application of stimulus blocks [John E. SWETTand Charles M. Bourassa. Electrical stimulation of peripheral nerve. In:Electrical Stimulation Research Techniques, Michael M. Patterson andRaymond P. Kesner, eds. Academic Press. (New York, 1981) pp. 243-295].

To date, the selection of stimulation waveform parameters for nervestimulation has been highly empirical, in which the parameters arevaried about some initially successful set of parameters, in an effortto find an improved set of parameters for each patient. A more efficientapproach to selecting stimulation parameters might be to select astimulation waveform that mimics electrical activity in the anatomicalregions that one is attempting stimulate indirectly, in an effort toentrain the naturally occurring electrical waveform, as suggested inU.S. Pat. No. 6,234,953, entitled Electrotherapy device using lowfrequency magnetic pulses, to THOMAS et al. and application numberUS20090299435, entitled Systems and methods for enhancing or affectingneural stimulation efficiency and/or efficacy, to GLINER et al. One mayalso vary stimulation parameters iteratively, in search of an optimalsetting [U.S. Pat. No. 7,869,885, entitled Threshold optimization fortissue stimulation therapy, to BEGNAUD et al]. However, some stimulationwaveforms, such as those described herein, are discovered by trial anderror, and then deliberately improved upon.

Invasive nerve stimulation typically uses square wave pulse signals.However, Applicant found that square waveforms are not ideal fornon-invasive stimulation as they produce excessive pain. Prepulses andsimilar waveform modifications have been suggested as methods to improveselectivity of nerve stimulation waveforms, but Applicant did not findthem ideal [Aleksandra VUCKOVIC, Marco Tosato and Johannes J Struijk. Acomparative study of three techniques for diameter selective fiberactivation in the vagal nerve: anodal block, depolarizing prepulses andslowly rising pulses. J. Neural Eng. 5 (2008): 275-286; AleksandraVUCKOVIC, Nico J. M. Rijkhoff, and Johannes J. Struijk. Different PulseShapes to Obtain Small Fiber Selective Activation by Anodal Blocking—ASimulation Study. IEEE Transactions on Biomedical Engineering 51(5,2004):698-706; Kristian HENNINGS. Selective Electrical Stimulation ofPeripheral Nerve Fibers: Accommodation Based Methods. Ph.D. Thesis,Center for Sensory-Motor Interaction, Aalborg University, Aalborg,Denmark, 2004].

Applicant also found that stimulation waveforms consisting of bursts ofsquare pulses are not ideal for non-invasive stimulation [M. I. JOHNSON,C. H. Ashton, D. R. Bousfield and J. W. Thompson. Analgesic effects ofdifferent pulse patterns of transcutaneous electrical nerve stimulationon cold-induced pain in normal subjects. Journal of PsychosomaticResearch 35 (2/3, 1991):313-321; U.S. Pat. No. 7,734,340, entitledStimulation design for neuromodulation, to De Ridder]. However, burstsof sinusoidal pulses are a preferred stimulation waveform, as shown inFIGS. 2D and 2E. As seen there, individual sinusoidal pulses have aperiod of τ, and a burst consists of N such pulses. This is followed bya period with no signal (the inter-burst period). The pattern of a burstfollowed by silent inter-burst period repeats itself with a period of T.For example, the sinusoidal period τ may be 200 microseconds; the numberof pulses per burst may be N=5; and the whole pattern of burst followedby silent inter-burst period may have a period of T=40000 microseconds,which is comparable to 25 Hz stimulation (a much smaller value of T isshown in FIG. 2E to make the bursts discernable). When these exemplaryvalues are used for T and τ, the waveform contains significant Fouriercomponents at higher frequencies ( 1/200 microseconds=5000/sec), ascompared with those contained in transcutaneous nerve stimulationwaveforms, as currently practiced.

Applicant is unaware of such a waveform having been used with vagusnerve stimulation, but a similar waveform has been used to stimulatemuscle as a means of increasing muscle strength in elite athletes.However, for the muscle strengthening application, the currents used(200 mA) may be very painful and two orders of magnitude larger thanwhat are disclosed herein. Furthermore, the signal used for musclestrengthening may be other than sinusoidal (e.g., triangular), and theparameters τ, N, and T may also be dissimilar from the valuesexemplified above [A. DELITTO, M. Brown, M. J. Strube, S. J. Rose, andR. C. Lehman. Electrical stimulation of the quadriceps femoris in anelite weight lifter: a single subject experiment. Int J Sports Med10(1989):187-191; Alex R WARD, Nataliya Shkuratova. Russian ElectricalStimulation: The Early Experiments. Physical Therapy 82 (10, 2002):1019-1030; Yocheved LAUFER and Michal Elboim. Effect of Burst Frequencyand Duration of Kilohertz-Frequency Alternating Currents and ofLow-Frequency Pulsed Currents on Strength of Contraction, MuscleFatigue, and Perceived Discomfort. Physical Therapy 88 (10,2008):1167-1176; Alex R WARD. Electrical Stimulation UsingKilohertz-Frequency Alternating Current. Physical Therapy 89 (2,2009):181-190; J. PETROFSKY, M. Laymon, M. Prowse, S. Gunda, and J.Batt. The transfer of current through skin and muscle during electricalstimulation with sine, square, Russian and interferential waveforms.Journal of Medical Engineering and Technology 33 (2, 2009): 170-181;U.S. Pat. No. 4,177,819, entitled Muscle stimulating apparatus, toKOFSKY et al]. Burst stimulation has also been disclosed in connectionwith implantable pulse generators, but wherein the bursting ischaracteristic of the neuronal firing pattern itself [U.S. Pat. No.7,734,340 to D E RIDDER, entitled Stimulation design forneuromodulation; application US20110184486 to D E RIDDER, entitledCombination of tonic and burst stimulations to treat neurologicaldisorders]. By way of example, the electric field shown in FIGS. 2D and2E may have an E_(max) value of 17 V/m, which is sufficient to stimulatethe nerve but is significantly lower than the threshold needed tostimulate surrounding muscle.

High frequency electrical stimulation is also known in the treatment ofback pain at the spine [Patent application US20120197369, entitledSelective high frequency spinal cord modulation for inhibiting pain withreduced side effects and associated systems and methods, to ALATARIS etal.; Adrian A L KAISY, Iris Smet, and Jean-Pierre Van Buyten. Analgeiaof axial low back pain with novel spinal neuromodulation. Posterpresentation #202 at the 2011 meeting of The American Academy of PainMedicine, held in National Harbor, Md., Mar. 24-27, 2011].

Those methods involve high-frequency modulation in the range of fromabout 1.5 KHz to about 50 KHz, which is applied to the patient's spinalcord region. However, such methods are different from the presentinvention because, for example, they are invasive; they do not involve abursting waveform, as in the present invention; they necessarily involveA-delta and C nerve fibers and the pain that those fibers produce,whereas the present invention does not; they may involve a conductionblock applied at the dorsal root level, whereas the present inventionmay stimulate action potentials without blocking of such actionpotentials; and/or they involve an increased ability of high frequencymodulation to penetrate through the cerebral spinal fluid, which is notrelevant to the present invention. In fact, a likely explanation for thereduced back pain that is produced by their use of frequencies from 10to 50 KHz is that the applied electrical stimulus at those frequenciescauses permanent damage to the pain-causing nerves, whereas the presentinvention involves only reversible effects [LEE R C, Zhang D, Hannig J.Biophysical injury mechanisms in electrical shock trauma. Annu RevBiomed Eng 2(2000):477-509].

The use of feedback to generate the modulation signal 400 may result ina signal that is not periodic, particularly if the feedback is producedfrom sensors that measure naturally occurring, time-varying aperiodicphysiological signals from the patient (see FIG. 15). In fact, theabsence of significant fluctuation in naturally occurring physiologicalsignals from a patient is ordinarily considered to be an indication thatthe patient is in ill health. This is because a pathological controlsystem that regulates the patient's physiological variables may havebecome trapped around only one of two or more possible steady states andis therefore unable to respond normally to external and internalstresses. Accordingly, even if feedback is not used to generate themodulation signal 400, it may be useful to artificially modulate thesignal in an aperiodic fashion, in such a way as to simulatefluctuations that would occur naturally in a healthy individual. Thus,the noisy modulation of the stimulation signal may cause a pathologicalphysiological control system to be reset or undergo a non-linear phasetransition, through a mechanism known as stochastic resonance. In normalrespiratory physiology, sighing at irregular intervals is thought tobring about such a resetting of the respiratory control system.Experimentally, noisy artificial ventilation may increase respiration[B. SUKI, A. Alencar, M. K. Sujeer, K. R. Lutchen, J. J. Collins, J. S.Andrade, E. P. Ingenito, S. Zapperi, H. E. Stanley, Life-support systembenefits from noise, Nature 393 (1998) 127-128; W Alan C MUTCH, M RuthGraham, Linda G Girling and John F Brewster. Fractal ventilationenhances respiratory sinus arrhythmia. Respiratory Research 2005, 6:41].

So, in one embodiment of the present invention, the modulation signal400, with or without feedback, will stimulate the selected nerve fibersin such a way that one or more of the stimulation parameters (power,frequency, and others mentioned herein) are varied by sampling astatistical distribution having a mean corresponding to a selected, orto a most recent running-averaged value of the parameter, and thensetting the value of the parameter to the randomly sampled value. Thesampled statistical distributions will comprise Gaussian and 1/f,obtained from recorded naturally occurring random time series or bycalculated formula. Parameter values will be so changed periodically, orat time intervals that are themselves selected randomly by samplinganother statistical distribution, having a selected mean and coefficientof variation, where the sampled distributions comprise Gaussian andexponential, obtained from recorded naturally occurring random timeseries or by calculated formula.

In another embodiment, devices in accordance with the present inventionare provided in a “pacemaker” type form, in which electrical impulses410 are generated to a selected region of the nerve by a stimulatordevice on an intermittent basis to create in the patient a lowerreactivity of the nerve.

Applicant's Animal Experiments Demonstrating that the DisclosedStimulation Waveform and Devices Bring about Bronchodilation byParticular Physiological Mechanisms

Applicant performed animal experiments using invasive methods in anattempt to (1) demonstrate that it is in fact possible to stimulate thevagus nerve to produce bronchodilation without first producingbronchoconstriction, and (2) elucidate physiological mechanisms that mayexplain such bronchodilation. Such animal experiments were thenperformed using noninvasive vagus nerve stimulation, as now described.

Inhibition of Histamine-Induced Bronchoconstriction in Guinea Pig andSwine by Pulsed Electrical Vagal Nerve Stimulation

A first set of experiments was performed to determine whether applying alow-voltage electrical signal to the vagus nerve could reducehistamine-induced bronchoconstriction in swine and guinea pigs. Sixteenguinea pigs were anesthetized and had bipolar electrodes positioned onthe cervical vagus nerves. Intravenous histamine was titrated to elicita moderate increase in pulmonary inflation pressure (Ppi). Histamine wasthen administered with or without concurrent vagus nerve stimulation(VNS).

The results are illustrated in FIG. 3. In FIG. 3A, an animal's airwaypressure is shown as a function of time, and at intervals shown there,bronchoconstriction was induced using a brief histamine challenge. Withhistamine alone as the intervention, the challenge is seen to producesignificant increases of airway pressure, but when the challenge isperformed in combination with stimulation of the vagus nerve (VNS)according to the present invention, a significantly smaller increase ofairway pressure is observed. FIG. 3B shows the results of a successionof such challenges in a single animal. As seen there, the magnitude ofthe increase is variable, but a challenge that includes VNS almostinvariably results in a smaller increase in airway pressure than achallenge with histamine alone. Results like those shown in FIG. 3B areshown in FIG. 3C for sixteen animals. As seen there, the magnitude ofthe air pressure increase varies from animal to animal, but almostinvariably, when VNS is included with the challenge, the result is asmaller increase in airway pressure than a challenge with histaminealone. In general, VNS reduced the peak change in Ppi following ahistamine challenge by approximately 60%.

Similar results were confirmed in a study in swine, demonstrating thatthe VNS procedure is applicable to larger animals as well. These studiessuggest that VNS can reduce bronchoconstriction and may prove useful asa therapy in the treatment of reactive airway disease [HOFFMANN, T. J.,Mendez, S., Staats, P., Emala, C. W., Guo, P. Inhibition ofhistamine-induced bronchoconstriction in guinea pig and swine by pulsedelectrical vagus nerve stimulation. Neuromodulation 12(4,2009):261-269].

Low Voltage Vagal Nerve Stimulation Reduces Bronchoconstriction inGuinea Pigs Through Catecholamine Release.

A second set of experiments was performed to evaluate the mechanism ofaction by which VNS reduces bronchoconstriction in guinea pigs. UnderIACUC approved protocols, male Hartley guinea pigs were anesthetizedwith urethane and ventilated by tracheostomy. Bronchoconstriction wasinduced via intravenous histamine or acetylcholine with or withoutsimultaneous, bilateral VNS at 25 Hz, 200 ms, 1-3 V. Airway pressurerecordings that are similar to those shown in FIG. 3A were made.Low-voltage VNS was found to attenuate histamine-inducedbronchoconstriction (4.4±0.3 vs. 3.2±0.2 cm H2O, p<0.01). Selectiveantagonists (L-NAME for iNANC nerve fibers, propranolol for sympatheticnerve fibers), sympathetic nerve depletion with guanethidine, and vagalligation were then used to elucidate neural pathways that may beresponsible for the bronchodilation or anti-bronchoconstrictionresponse. The results of these animal studies were as follows.

Blockade of nitric oxide synthesis by pretreatment with L-NAME (aprimary mediator of inhibitory non-adrenergic, non-cholinergic (iNANC)bronchodilator pathways) had little or no effect on VNS-mediatedattenuation of bronchoconstriction. Sympathetic nerve depletion withguanethidine also had little or no effect on VNS-mediated attenuation ofbronchoconstriction. However, pretreatment with propranolol didreversibly blocked the effect. As shown in FIG. 4A, without pretreatmentwith propranolol, the effect of VNS at the indicated times was to reducethe magnitude of bronchoconstriction produced by histamine (H) that wasadministered at the indicated times. However, when propranolol wasadministered as a pretreatment, as shown in FIG. 4B, the VNS-mediatedattenuation of bronchoconstriction was blocked.

Ligating both cephalic vagus nerves caudal to the stimulating electrodesdid not block VNS-mediated attenuation of bronchoconstriction, butligating the vagus nerves between the electrodes and head did block theattenuation of bronchoconstriction (FIG. 4D) as compared with thesituation prior to ligation (FIG. 4C). These unexpected findings suggestthat VNS could inhibit bronchoconstriction through a purely afferentvagus pathway, but not a purely efferent vagus pathway. We also foundthat low-voltage VNS increased circulating epinephrine andnorepinephrine. These results indicate that low-voltage VNS attenuateshistamine-induced bronchoconstriction via activation of afferent nerves,in part by producing a systemic increase in catecholamines likelyarising from the adrenal medulla. Furthermore, we tested whether theattenuation by VNS of histamine-induced increases in Ppi was mediated bydirect efferent stimulation of sympathetic nerve fibers traveling withinthe cervical vagus nerve or by stimulation of parasympathetic iNANCnerves in the guinea pig lung. Our results rule out both of thesepossibilities since ligation of the vagal nerve caudal to the electrodesdid not eliminate the bronchoprotection afforded by low-voltage VNS.Moreover, pretreatment with guanethidine or L-NAME to blocknorepinephrine or nitric oxide release from sympathetic or iNANC nerves,respectively, did not block the bronchoprotection afforded bylow-voltage VNS. Although we demonstrated that the VNS-mediatedattenuation of bronchoconstriction involves the participation of vagalafferent nerves (and therefore the central nervous system), and thatsympathetic non-vagal efferent pathways were also implicated in themechanisms, the design of the experiments was such that efferent signalssent from the central nervous system to the lungs via the vagus nerve,other than those involving sympathetic or iNANC nerves, were notinvestigated separately. In that regard, we can conclude only that VNSstimulation between a ligated vagus nerve and the lung did not attenuatebronchoconstriction, with the understanding that such a ligated nerve isnot conveying signals to the lung from the central nervous system.

To ensure that the dissection and placement of the stimulation leadsdirect to the vagus nerve had not damaged the nerve, the amplitude ofthe applied signal was increased significantly beyond the anticipatedtherapeutic level until the classic vaso-vagal responses of bradycardiaand bronchoconstriction were observed. We found that in the guinea pigmodel, stimulation of efferent C-fibers causing both bradycardia andbronchoconstriction could only be achieved at voltages 10×-20× greaterthan those that were used to inhibit bronchoconstriction [HOFFMANN, T.J., Simon, B. J., Zhang, Y., Emala, C. W. Low-Voltage Vagal NerveStimulation Reduces Bronchoconstriction in Guinea Pigs ThroughCatecholamine Release. Neuromodulation. 2012 May 2. doi:10.1111/j.1525-1403.2012.00454.x.; a preliminary version of this workwas published in the following conference proceedings: Bruce J. SIMON,Charles W. Emala, Lawrence M. Lewis, Daniel Theodoro, YaninaPurim-Shem-Tov, Pedro Sepulveda, Thomas J. Hoffmann, Peter Staats. VagalNerve Stimulation for Relief of Bronchoconstriction: PreliminaryClinical Data and Mechanism of Action. Proceedings page 119 ofNeuromodulation: 2010 and Beyond; North American Neuromodulation Society13th Annual Meeting, Dec. 3-6, 2009].

These preliminary animal data indicate that VNS activates afferentnerves and may act through a sympathetic reflex pathway to mediatebronchodilation. Thus, we found that bronchodilation resulting fromstimulation of the vagus nerve works by causing the systemic release ofthe natural, endogenous β-agonists, epinephrine and norepinephrine.These catecholamines can reach the constricted bronchial smooth musclethrough an internal, systemic pathway, thereby overcoming any potentialproblems with inhaled β-agonists, for example, due to mucus congestion.The electrical field delivered to the vagus nerve was optimized tostimulate the release of these hormones into the circulation atconcentrations that produce bronchial smooth muscle relaxation, but havelittle effect on heart rate or blood pressure. The data suggest that therelease of these catecholamines is mediated by a parasympathetic,afferent vagal signal to the brain, which then triggers an efferentsympathetic signal to stimulate the release of catecholamines from theadrenal glands. These animal data show that the stimulator is effectiveeven if the vagus nerve is tied off distal to the electrode and that thebronchodilation effect can be blocked with the β-blocker propranolol. Inaddition, stimulation was found to be ineffective in animals that havehad their adrenal glands removed.

Evaluation of Noninvasive Vagal Nerve Stimulation in Ragweed SensitizedBeagle Dogs: Methacholine Induced Bronchoconstriction.

Noninvasive VNS was developed and tested in an establishedhypersensitive beagle asthma model to confirm that the noninvasive VNShad a safety and efficacy profile similar to percutaneous VNS. Thestimulating device was similar to one shown in FIGS. 2A and 6 (known bythe inventors as the AlphaCore® device). Dogs were subjected tomethacholine (Mch) challenges inducing ˜100% increase in airwayresistance (FIG. 5, black bar). Dogs were then treated with noninvasiveVNS for 90 to 120 seconds (2 min). Treatment with noninvasive VNSresulted in a significant reduction in Mch-induced bronchoconstriction,which occurred within 1 minute of the VNS (FIG. 5, barber-pole bar).

Subsequent to the noninvasive VNS stimulation, the dogs were repeatedlychallenged with the same dose of Mch at 15, 30, 60, 90, and 120 minutes.Noninvasive VNS effects lasted for up to 2 hours, through 5 additionalchallenges without additional VNS stimulations required, with nosignificant changes in blood pressure or heart rate. These results arecomparable at the same time points to results obtained with high-dosealbuterol (a bronchodilator medication, instead of VNS) in the samebeagle model (FIG. 5, at the indicated time points). In a secondexperiment propranolol was given intravenously prior to either albuterolor noninvasive VNS, resulting in a significant reduction inmethacholine-induced bronchoconstriction. We conclude from theseexperiments that the foregoing results that we had obtained inexperiments involving invasive VNS may be extrapolated to the presentinvention involving noninvasive VNS.

Consider now which nerve fibers may be stimulated by the non-invasivevagus nerve stimulation. The waveform disclosed in FIG. 2 containssignificant Fourier components at high frequencies (e.g., 1/200microseconds=5000/sec), even if the waveform also has components atlower frequencies (e.g., 25/sec). Transcutaneously, A-beta, A-delta, andC fibers are typically excited at 2000 Hz, 250 Hz, and 5 Hz,respectively, i.e., the 2000 Hz stimulus is described as being specificfor measuring the response of A-beta fibers, the 250 Hz for A-deltafibers, and the 5 Hz for type C fibers [George D. BAQUIS et al.TECHNOLOGY REVIEW: THE NEUROMETER CURRENT PERCEPTION THRESHOLD (CPT).Muscle Nerve 22(Supplement 8, 1999): S247-5259]. Therefore, the highfrequency component of the noninvasive stimulation waveform willpreferentially stimulate the A-alpha and A-beta fibers, and the C fiberswill be largely unstimulated.

However, the threshold for activation of fiber types also depends on theamplitude of the stimulation, and for a given stimulation frequency, thethreshold increases as the fiber size decreases. The threshold forgenerating an action potential in nerve fibers that are impaled withelectrodes is traditionally described by Lapicque or Weiss equations,which describe how together the width and amplitude of stimulus pulsesdetermine the threshold, along with parameters that characterize thefiber (the chronaxy and rheobase). For nerve fibers that are stimulatedby electric fields that are applied externally to the fiber, as is thecase here, characterizing the threshold as a function of pulse amplitudeand frequency is more complicated, which ordinarily involves thenumerical solution of model differential equations or a case-by-caseexperimental evaluation [David BOINAGROV, Jim Loudin and DanielPalanker. Strength-Duration Relationship for Extracellular NeuralStimulation: Numerical and Analytical Models. J Neurophysiol104(2010):2236-2248].

For example, REILLY describes a model (the spatially extended nonlinearnodal model or SENN model) that may be used to calculate minimumstimulus thresholds for nerve fibers having different diameters [J.Patrick REILLY. Electrical models for neural excitation studies. JohnsHopkins APL Technical Digest 9(1, 1988): 44-59]. According to REILLY'sanalysis, the minimum threshold for excitation of myelinated A fibers is6.2 V/m for a 20 μm diameter fiber, 12.3 V/m for a 10 μm fiber, and 24.6V/m for a 5 μm diameter fiber, assuming a pulse width that is within thecontemplated range of the present invention (1 ms). It is understoodthat these thresholds may differ slightly from those produced by thewaveform of the present invention as illustrated by REILLY's figures,for example, because the present invention prefers to use sinusoidalrather than square pulses. Thresholds for B and C fibers arerespectively 2 to 3 and 10 to 100 times greater than those for A fibers[Mark A. CASTORO, Paul B. Yoo, Juan G. Hincapie, Jason J. Hamann,Stephen B. Ruble, Patrick D. Wolf, Warren M. Grill. Excitationproperties of the right cervical vagus nerve in adult dogs. ExperimentalNeurology 227 (2011): 62-68]. If we assume an average A fiber thresholdof 15 V/m, then B fibers would have thresholds of 30 to 45 V/m and Cfibers would have thresholds of 150 to 1500 V/m. The present inventionproduces electric fields at the vagus nerve in the range of about 6 to100 V/m, which is therefore generally sufficient to excite allmyelinated A and B fibers, but not the unmyelinated C fibers. Incontrast, invasive vagus nerve stimulators that have been used for thetreatment of epilepsy have been reported to excite C fibers in somepatients [EVANS M S, Verma-Ahuja S, Naritoku D K, Espinosa J A.Intraoperative human vagus nerve compound action potentials. Acta NeurolScand 110(2004): 232-238].

It is understood that although devices of the present invention maystimulate A and B nerve fibers, in practice they may also be used so asnot to stimulate the largest A fibers (A-delta) and B fibers. Inparticular, if the stimulator amplitude has been increased to the pointat which unwanted side effects begin to occur, the operator of thedevice may simply reduce the amplitude to avoid those effects. Forexample, vagal efferent fibers responsible for bronchoconstriction havebeen observed to have conduction velocities in the range of those of Bfibers. In those experiments, bronchoconstriction was only produced whenB fibers were activated, and became maximal before C fibers had beenrecruited [R. M. McALLEN and K. M. Spyer. Two types of vagalpreganglionic motoneurones projecting to the heart and lungs. J.Physiol. 282(1978): 353-364]. Because proper stimulation with thedisclosed devices does not result in bronchoconstriction, evidently thebronchoconstrictive B-fibers are possibly not being activated when theamplitude is properly set. Also, the absence of bradycardia orprolongation of PR interval suggests that cardiac efferent B-fibers arenot stimulated. Similarly, the jugular A-delta fibers are RAR-likeafferents that behave physiologically like C fibers. Because stimulationwith the disclosed devices does not produce nociceptive effects thatwould be produced by jugular A-delta fibers or C fibers, evidently theA-delta fibers may not be stimulated when the amplitude is properly set.

To summarize the foregoing discussion, the delivery, in a patientsuffering from severe asthma, COPD, anaphylactic shock, or otherbronchoconstrictive exacerbation, of an impulse of energy sufficient tostimulate, block and/or modulate transmission of signals of vagus nervefibers will result in relaxation of the bronchial smooth muscle,dilating airways. The most likely mechanisms do not involve thestimulation of C fibers; bronchodilation resulting from stimulation ofthe vagus nerve works in part by causing the systemic release of thenatural, endogenous β-agonists from the adrenal medulla; and thestimulation of afferent A and B nerve fibers of the vagus nerveactivates neural pathways causing the release of norepinephrine, and/orserotonin and/or GABA onto airway-related vagal preganglionic neurons(AVPNs), thereby antagonizing bronchoconstriction that is mediated bycholinergic nerve fibers. In addition, the release of these inhibitoryneurotransmitters causes an inhibition of mucous production in themucous glands within the airway passages.

Stimulating, blocking and/or modulating the signal in selected nerves toreduce parasympathetic tone provides an immediate emergency response,much like a defibrillator, in situations of severe asthma or COPDattacks or anaphylactic shock, providing immediate temporary dilation ofthe airways and optionally an increase of heart function untilsubsequent measures, such as administration of epinephrine, rescuebreathing and intubation can be employed. Treatment in accordance withthe present invention provides bronchodilation and possibly increasedheart function for a long enough period of time so that administeredmedication such as epinephrine has time to take effect before thepatient suffocates.

Preferred Embodiment of the Magnetic Stimulator

A preferred embodiment of magnetic stimulator coil 341 comprises atoroidal winding around a core consisting of high-permeability material(e.g., Supermendur), embedded in an electrically conducting medium.Toroidal coils with high permeability cores have been theoreticallyshown to greatly reduce the currents required for transcranial (TMS) andother forms of magnetic stimulation, but only if the toroids areembedded in a conducting medium and placed against tissue with no airinterface. [Rafael CARBUNARU and Dominique M. Durand. Toroidal coilmodels for transcutaneous magnetic stimulation of nerves. IEEETransactions on Biomedical Engineering 48 (4, 2001): 434-441; RafaelCarbunaru FAIERSTEIN, Coil Designs for Localized and Efficient MagneticStimulation of the Nervous System. Ph.D. Dissertation, Department ofBiomedical Engineering, Case Western Reserve, May, 1999, (UMI MicroformNumber: 9940153, UMI Company, Ann Arbor Mich.)].

Although Carbunaru and Durand demonstrated that it is possible toelectrically stimulate a patient transcutaneously with such a device,they made no attempt to develop the device in such a way as to generallyshape the electric field that is to stimulate the nerve. In particular,the electric fields that may be produced by their device are limited tothose that are radially symmetric at any given depth of stimulation intothe patient (i.e., z and p are used to specify location of the field,not x, y, and z). This is a significant limitation, and it results in adeficiency that was noted in FIG. 6 of their publication: “at largedepths of stimulation, the threshold current [in the device's coil] forlong axons is larger than the saturation current of the coil.Stimulation of those axons is only possible at low threshold points suchas bending sites or tissue conductivity inhomogeneities”. Thus, fortheir device, varying the parameters that they considered, in order toincrease the electric field or its gradient in the vicinity of a nerve,may come at the expense of limiting the field's physiologicaleffectiveness, such that the spatial extent of the field of stimulationmay be insufficient to modulate the target nerve's function. Yet, suchlong axons are precisely what we may wish to stimulate in therapeuticinterventions, such as the ones disclosed herein.

Accordingly, it is an objective of the present invention to shape anelongated electric field of effect that can be oriented parallel to sucha long nerve. The term “shape an electric field” as used herein means tocreate an electric field or its gradient that is generally not radiallysymmetric at a given depth of stimulation in the patient, especially afield that is characterized as being elongated or finger-like, andespecially also a field in which the magnitude of the field in somedirection may exhibit more than one spatial maximum (i.e. may be bimodalor multimodal) such that the tissue between the maxima may contain anarea across which induced current flow is restricted. Shaping of theelectric field refers both to the circumscribing of regions within whichthere is a significant electric field and to configuring the directionsof the electric field within those regions. The shaping of the electricfield is described in terms of the corresponding field equations incommonly assigned application US20110125203 (application Ser. No.12/964,050), entitled Magnetic stimulation devices and methods oftherapy, to SIMON et al., which is hereby incorporated by reference.Thus, the present invention differs from the device disclosed byCARBUNARU and Durand by deliberately shaping an electric field that isused to transcutaneously stimulate the patient. Whereas the toroid inthe CARBUNARU and Durand publication was immersed in a homogeneousconducting half-space, this is not necessarily the case for ourinvention. Although our invention will generally have some continuouslyconducting path between the device's coil and the patient's skin, theconducting medium need not totally immerse the coil, and there may beinsulating voids within the conducting medium. For example, if thedevice contains two toroids, conducting material may connect each of thetoroids individually to the patient's skin, but there may be aninsulating gap (from air or some other insulator) between the surfacesat which conducting material connected to the individual toroids contactthe patient. Furthermore, the area of the conducting material thatcontacts the skin may be made variable, by using an aperture adjustingmechanism such as an iris diaphragm. As another example, if the coil iswound around core material that is laminated, with the core in contactwith the device's electrically conducting material, then the laminationmay be extended into the conducting material in such a way as to directthe induced electrical current between the laminations and towards thesurface of the patient's skin. As another example, the conductingmaterial may pass through apertures in an insulated mesh beforecontacting the patient's skin, creating thereby an array of electricfield maxima. In the dissertation cited above, Carbunaru—FAIERSTEIN madeno attempt to use conducting material other than agar in a KCl solution,and he made no attempt to devise a device that could be conveniently andsafely applied to a patient's skin, at an arbitrary angle without theconducting material spilling out of its container. It is therefore anobjective of the present invention to disclose conducting material thatcan be used not only to adapt the conductivity of the conductingmaterial and select boundary conditions, thereby shaping the electricfields and currents as described above, but also to create devices thatcan be applied practically to any surface of the body. The volume of thecontainer containing electrically conducting medium is labeled in FIG. 2as 351. Use of the container of conducting medium 351 allows one togenerate (induce) electric fields in tissue (and electric fieldgradients and electric currents) that are equivalent to those generatedusing current magnetic stimulation devices, but with about 0.001 to 0.1of the current conventionally applied to a magnetic stimulation coil.This allows for minimal heating of the coil(s) and deeper tissuestimulation. However, application of the conducting medium to thesurface of the patient is difficult to perform in practice because thetissue contours (head, arms, legs, neck, etc.) are not planar. To solvethis problem, in the preferred embodiment of the present invention, thetoroidal coil is embedded in a structure which is filled with aconducting medium having approximately the same conductivity as muscletissue, as now described.

In one embodiment of the invention, the container contains holes so thatthe conducting material (e.g., a conducting gel) can make physicalcontact with the patient's skin through the holes. For example, theconducting medium 351 may comprise a chamber surrounding the coil,filled with a conductive gel that has the approximate viscosity andmechanical consistency of gel deodorant (e.g., Right Guard Clear Gelfrom Dial Corporation, 15501 N. Dial Boulevard, Scottsdale Ariz. 85260,one composition of which comprises aluminum chlorohydrate, sorbitol,propylene glycol, polydimethylsiloxanes Silicon oil, cyclomethicone,ethanol/SD Alcohol 40, dimethicone copolyol, aluminum zirconiumtetrachlorohydrex gly, and water). The gel, which is less viscous thanconventional electrode gel, is maintained in the chamber with a mesh ofopenings at the end where the device is to contact the patient's skin.The gel does not leak out, and it can be dispensed with a simple screwdriven piston.

In another embodiment, the container itself is made of a conductingelastomer (e.g., dry carbon-filled silicone elastomer), and electricalcontact with the patient is through the elastomer itself, possiblythrough an additional outside coating of conducting material. In someembodiments of the invention, the conducting medium may be a balloonfilled with a conducting gel or conducting powders, or the balloon maybe constructed extensively from deformable conducting elastomers. Theballoon conforms to the skin surface, removing any air, thus allowingfor high impedance matching and conduction of large electric fields into the tissue. A device such as that disclosed in U.S. Pat. No.7,591,776, entitled Magnetic stimulators and stimulating coils, toPHILLIPS et al. may conform the coil itself to the contours of the body,but in the preferred embodiment, such a curved coil is also enclosed bya container that is filled with a conducting medium that deforms to becontiguous with the skin.

Agar can also be used as part of the conducting medium, but it is notpreferred, because agar degrades in time, is not ideal to use againstskin, and presents difficulties with cleaning the patient and stimulatorcoil. Use of agar in a 4M KCl solution as a conducting medium wasmentioned in the above-cited dissertation: Rafael Carbunaru FAIERSTEIN,Coil Designs for Localized and Efficient Magnetic Stimulation of theNervous System. Ph.D. Dissertation, Department of BiomedicalEngineering, Case Western Reserve, May, 1999, page 117 (UMI MicroformNumber: 9940153, UMI Company, Ann Arbor Mich.). However, thatpublication makes no mention or suggestion of placing the agar in aconducting elastomeric balloon, or other deformable container so as toallow the conducting medium to conform to the generally non-planarcontours of a patient's skin having an arbitrary orientation. In fact,that publication describes the coil as being submerged in a containerfilled with an electrically conducting solution. If the coil andcontainer were placed on a body surface that was oriented in thevertical direction, then the conducting solution would spill out, makingit impossible to stimulate the body surface in that orientation. Incontrast, the present invention is able to stimulate body surfaceshaving arbitrary orientation.

That dissertation also makes no mention of a dispensing method wherebythe agar would be made contiguous with the patient's skin. A layer ofelectrolytic gel is said to have been applied between the skin and coil,but the configuration was not described clearly in the publication. Inparticular, no mention is made of the electrolytic gel being in contactwith the agar.

Rather than using agar as the conducting medium, the coil can instead beembedded in a conducting solution such as 1-10% NaCl, contacting anelectrically conducting interface to the human tissue. Such an interfaceis used as it allows current to flow from the coil into the tissue andsupports the medium-surrounded toroid so that it can be completelysealed. Thus, the interface is material, interposed between theconducting medium and patient's skin, that allows the conducting medium(e.g., saline solution) to slowly leak through it, allowing current toflow to the skin. Several interfaces are disclosed as follows.

One interface comprises conducting material that is hydrophilic, such asTecophlic from The Lubrizol Corporation, 29400 Lakeland Boulevard,Wickliffe, Ohio 44092. It absorbs from 10-100% of its weight in water,making it highly electrically conductive, while allowing only minimalbulk fluid flow.

Another material that may be used as an interface is a hydrogel, such asthat used on standard EEG, EKG and TENS electrodes [Rylie A GREEN,Sungchul Baek, Laura A Poole-Warren and Penny J Martens. Conductingpolymer-hydrogels for medical electrode applications. Sci. Technol. Adv.Mater. 11 (2010) 014107 (13 pp)]. For example it may be the followinghypoallergenic, bacteriostatic electrode gel: SIGNAGEL Electrode Gelfrom Parker Laboratories, Inc., 286 Eldridge Rd., Fairfield N.J. 07004.

A third type of interface may be made from a very thin material with ahigh dielectric constant, such as those used to make capacitors. Forexample, Mylar can be made in submicron thicknesses and has a dielectricconstant of about 3. Thus, at stimulation frequencies of severalkilohertz or greater, the Mylar will capacitively couple the signalthrough it because it will have an impedance comparable to that of theskin itself. Thus, it will isolate the toroid and the solution it isembedded in from the tissue, yet allow current to pass.

The preferred embodiment of the magnetic stimulator coil 341 in FIG. 2Areduces the volume of conducting material that must surround a toroidalcoil, by using two toroids, side-by-side, and passing electrical currentthrough the two toroidal coils in opposite directions. In thisconfiguration, the induced current will flow from the lumen of onetoroid, through the tissue and back through the lumen of the other,completing the circuit within the toroids' conducting medium. Thus,minimal space for the conducting medium is required around the outsideof the toroids at positions near from the gap between the pair of coils.An additional advantage of using two toroids in this configuration isthat this design will greatly increase the magnitude of the electricfield gradient between them, which is crucial for exciting long,straight axons such as the vagus nerve and certain other peripheralnerves.

This preferred embodiment of the invention is shown in FIG. 6. FIGS. 6Aand 6B respectively provide top and bottom views of the outer surface ofthe toroidal magnetic stimulator 30. FIGS. 6C and 6D respectivelyprovide top and bottom views of the toroidal magnetic stimulator 30,after sectioning along its long axis to reveal the inside of thestimulator.

FIGS. 6A-6D all show a mesh 31 with openings that permit a conductinggel to pass from the inside of the stimulator to the surface of thepatient's skin at the location of nerve or tissue stimulation. Thus, themesh with openings 31 is the part of the stimulator that is applied tothe skin of the patient.

FIGS. 6B-6D show openings at the opposite end of the stimulator 30. Oneof the openings is an electronics port 32 through which wires pass fromthe stimulator coil(s) to the impulse generator (310 in FIG. 2A). Thesecond opening is a conducting gel port 33 through which conducting gelmay be introduced into the stimulator 30 and through which ascrew-driven piston arm may be introduced to dispense conducting gelthrough the mesh 31. The gel itself will be contained withincylindrical-shaped but interconnected conducting medium chambers 34 thatare shown in FIGS. 6C and 6D. The depth of the conducting mediumchambers 34, which is approximately the height of the long axis of thestimulator, affects the magnitude of the electric fields and currentsthat are induced by the device [Rafael CARBUNARU and Dominique M.Durand. Toroidal coil models for transcutaneous magnetic stimulation ofnerves. IEEE Transactions on Biomedical Engineering. 48 (4, 2001):434-441].

FIGS. 6C and 6D also show the coils of wire 35 that are wound aroundtoroidal cores 36, consisting of high-permeability material (e.g.,Supermendur). Lead wires (not shown) for the coils 35 pass from thestimulator coil(s) to the impulse generator (310 in FIG. 1) via theelectronics port 32. Different circuit configurations are contemplated.If separate lead wires for each of the coils 35 connect to the impulsegenerator (i.e., parallel connection), and if the pair of coils arewound with the same handedness around the cores, then the design is forcurrent to pass in opposite directions through the two coils. On theother hand, if the coils are wound with opposite handedness around thecores, then the lead wires for the coils may be connected in series tothe impulse generator, or if they are connected to the impulse generatorin parallel, then the design is for current to pass in the samedirection through both coils.

As seen in FIGS. 6C and 6D, the coils 35 and cores 36 around which theyare wound are mounted as close as practical to the corresponding mesh 31with openings through which conducting gel passes to the surface of thepatient's skin. As seen in FIG. 6D, each coil and the core around whichit is wound is mounted in its own housing 37, the function of which isto provide mechanical support to the coil and core, as well as toelectrically insulate a coil from its neighboring coil. With thisdesign, induced current will flow from the lumen of one toroid, throughthe tissue and back through the lumen of the other, completing thecircuit within the toroids' conducting medium.

Different diameter toroidal coils and windings may be preferred fordifferent applications. For a generic application, the outer diameter ofthe core may be typically 1 to 5 cm, with an inner diameter typically0.5 to 0.75 of the outer diameter. The coil's winding around the coremay be typically 3 to 250 in number, depending on the core diameter anddepending on the desired coil inductance.

-   -   Signal generators for magnetic stimulators have been described        for commercial systems [Chris HOVEY and Reza Jalinous, THE GUIDE        TO MAGNETIC STIMULATION, The Magstim Company Ltd, Spring        Gardens, Whitland, Carmarthenshire, SA34 OHR, United Kingdom,        2006], as well as for custom designs for a control unit 330,        impulse generator 310 and power source 320 [Eric BASHAM, Zhi        Yang, Natalia Tchemodanov, and Wentai Liu. Magnetic Stimulation        of Neural Tissue: Techniques and System Design. pp 293-352, In:        Implantable Neural Prostheses 1, Devices and Applications, D.        Zhou and E. Greenbaum, eds., New York: Springer (2009); U.S.        Pat. No. 7,744,523, entitled Drive circuit for magnetic        stimulation, to Charles M. Epstein; U.S. Pat. No. 5,718,662,        entitled Apparatus for the magnetic stimulation of cells or        tissue, to Reza Jalinous; U.S. Pat. No. 5,766,124, entitled        Magnetic stimulator for neuro-muscular tissue, to Poison].        Conventional magnetic nerve stimulators use a high current        impulse generator that may produce discharge currents of 5,000        amps or more, which is passed through the stimulator coil, and        which thereby produces a magnetic pulse. Typically, a        transformer charges a capacitor in the impulse generator 310,        which also contains circuit elements that limit the effect of        undesirable electrical transients. Charging of the capacitor is        under the control of a control unit 330, which accepts        information such as the capacitor voltage, power and other        parameters set by the user, as well as from various safety        interlocks within the equipment that ensure proper operation,        and the capacitor is then discharged through the coil via an        electronic switch (e.g., a controlled rectifier) when the user        wishes to apply the stimulus.

Greater flexibility is obtained by adding to the impulse generator abank of capacitors that can be discharged at different times. Thus,higher impulse rates may be achieved by discharging capacitors in thebank sequentially, such that recharging of capacitors is performed whileother capacitors in the bank are being discharged. Furthermore, bydischarging some capacitors while the discharge of other capacitors isin progress, by discharging the capacitors through resistors havingvariable resistance, and by controlling the polarity of the discharge,the control unit may synthesize pulse shapes that approximate anarbitrary function.

The design and methods of use of impulse generators, control units, andstimulator coils for magnetic stimulators are informed by the designsand methods of use of impulse generators, control units, and electrodes(with leads) for comparable completely electrical nerve stimulators, butdesign and methods of use of the magnetic stimulators must take intoaccount many special considerations, making it generally notstraightforward to transfer knowledge of completely electricalstimulation methods to magnetic stimulation methods. Such considerationsinclude determining the anatomical location of the stimulation anddetermining the appropriate pulse configuration [OLNEY R K, So Y T,Goodin D S, Aminoff M J. A comparison of magnetic and electricstimulation of peripheral nerves. Muscle Nerve 1990:13:957-963; J.NILSSON, M. Panizza, B. J. Roth et al. Determining the site ofstimulation during magnetic stimulation of the peripheral nerve,Electroencephalographs and clinical neurophysiology. vol 85, pp.253-264, 1992; Nafia AL-MUTAWALY, Hubert de Bruin, and Gary Hasey. TheEffects of Pulse Configuration on Magnetic Stimulation. Journal ofClinical Neurophysiology 20(5):361-370, 2003].

Furthermore, a potential practical disadvantage of using magneticstimulator coils is that they may overheat when used over an extendedperiod of time. Use of the above-mentioned toroidal coil and containerof electrically conducting medium addresses this potential disadvantage.However, because of the poor coupling between the stimulating coils andthe nerve tissue, large currents are nevertheless required to reachthreshold electric fields. At high repetition rates, these currents canheat the coils to unacceptable levels in seconds to minutes depending onthe power levels and pulse durations and rates. Two approaches toovercome heating are to cool the coils with flowing water or air or toincrease the magnetic fields using ferrite cores (thus allowing smallercurrents). For some applications where relatively long treatment timesat high stimulation frequencies may be required, e.g. treating acuteasthma attacks by stimulating the vagus nerve, neither of these twoapproaches are adequate. Water-cooled coils overheat in a few minutes.Ferrite core coils heat more slowly due to the lower currents and heatcapacity of the ferrite core, but also cool off more slowly and do notallow for water-cooling since the ferrite core takes up the volume wherethe cooling water would flow.

A solution to this problem is to use a fluid which containsferromagnetic particles in suspension like a ferrofluid, ormagnetorheological fluid as the cooling material. Ferrofluids arecolloidal mixtures composed of nanoscale ferromagnetic, orferrimagnetic, particles suspended in a carrier fluid, usually anorganic solvent or water. The ferromagnetic nanoparticles are coatedwith a surfactant to prevent their agglomeration (due to van der Waalsforces and magnetic forces). Ferrofluids have a higher heat capacitythan water and will thus act as better coolants. In addition, the fluidwill act as a ferrite core to increase the magnetic field strength.Also, since ferrofluids are paramagnetic, they obey Curie's law, andthus become less magnetic at higher temperatures. The strong magneticfield created by the magnetic stimulator coil will attract coldferrofluid more than hot ferrofluid thus forcing the heated ferrofluidaway from the coil. Thus, cooling may not require pumping of theferrofluid through the coil, but only a simple convective system forcooling. This is an efficient cooling method which may require noadditional energy input [U.S. Pat. No. 7,396,326 and publishedapplications US2008/0114199, US2008/0177128, and US2008/0224808, allentitled Ferrofluid cooling and acoustical noise reduction in magneticstimulators, respectively to Ghiron et al., Riehl et al., Riehl et al.and Ghiron et al.].

Magnetorheological fluids are similar to ferrofluids but contain largermagnetic particles which have multiple magnetic domains rather than thesingle domains of ferrofluids. [U.S. Pat. No. 6,743,371, Magnetosensitive fluid composition and a process for preparation thereof, toJohn et al.]. They can have a significantly higher magnetic permeabilitythan ferrofluids and a higher volume fraction of iron to carrier.Combinations of magnetorheological and ferrofluids may also be used [M TLOPEZ-LOPEZ, P Kuzhir, S Lacis, G Bossis, F Gonzalez-Caballero and J D GDuran. Magnetorheology for suspensions of solid particles dispersed inferrofluids. J. Phys.: Condens. Matter 18 (2006) S2803-S2813; LadislauVEKAS. Ferrofluids and Magnetorheological Fluids. Advances in Scienceand Technology Vol. 54 (2008) pp 127-136.].

Commercially available magnetic stimulators include circular, parabolic,figure-of-eight (butterfly), and custom designs that are availablecommercially [Chris HOVEY and Reza Jalinous, THE GUIDE TO MAGNETICSTIMULATION, The Magstim Company Ltd, Spring Gardens, Whitland,Carmarthenshire, SA34 0HR, United Kingdom, 2006]. Additional embodimentsof the magnetic stimulator coil 341 have been described [U.S. Pat. No.6,179,770, entitled Coil assemblies for magnetic stimulators, to StephenMould; Kent DAVEY. Magnetic Stimulation Coil and Circuit Design. IEEETransactions on Biomedical Engineering, Vol. 47 (No. 11, November 2000):1493-1499]. Many of the problems that are associated with suchconventional magnetic stimulators, e.g., the complexity of theimpulse-generator circuitry and the problem with overheating, arelargely avoided by the toroidal design shown in FIG. 6.

Thus, use of the container of conducting medium 351 allows one togenerate (induce) electric fields in tissue (and electric fieldgradients and electric currents) that are equivalent to those generatedusing current magnetic stimulation devices, but with about 0.001 to 0.1of the current conventionally applied to a magnetic stimulation coil.Therefore, with the present invention, it is possible to generatewaveforms shown in FIG. 2 with relatively simple, low-power circuitsthat are powered by batteries. The circuits may be enclosed within a box38 as shown in FIG. 6E, or the circuits may be attached to thestimulator itself (FIG. 6A-6D) to be used as a hand-held device. Ineither case, control over the unit may be made using only an on/offswitch and power knob. The only other component that may be needed mightbe a cover 39 to keep the conducting fluid from leaking or drying outbetween uses. The currents passing through the coils of the magneticstimulator will saturate its core (e.g., 0.1 to 2 Tesla magnetic fieldstrength for Supermendur core material). This will require approximately0.5 to 20 amperes of current being passed through each coil, typically 2amperes, with voltages across each coil of 10 to 100 volts. The currentis passed through the coils in bursts of pulses, as described inconnection with FIGS. 2D and 2E, shaping an elongated electrical fieldof effect.

Preferred Embodiment of the Electrode-Based Stimulator

In another embodiment of the invention, electrodes applied to thesurface of the neck, or to some other surface of the body, are used tonon-invasively deliver electrical energy to a nerve, instead ofdelivering the energy to the nerve via a magnetic coil. The vagus nervehas been stimulated previously non-invasively using electrodes appliedvia leads to the surface of the skin. For example, U.S. Pat. No.7,340,299, entitled Methods of indirectly stimulating the vagus nerve toachieve controlled asystole, to John D. PUSKAS, discloses thestimulation of the vagus nerve using electrodes placed on the neck ofthe patient, but that patent is unrelated to the treatment ofbronchoconstriction. Non-invasive electrical stimulation of the vagusnerve has also been described in Japanese patent applicationJP2009233024A with a filing date of Mar. 26, 2008, entitled Vagus NerveStimulation System, to Fukui YOSHIHOTO, in which a body surfaceelectrode is applied to the neck to stimulate the vagus nerveelectrically. However, that application pertains to the control of heartrate and is unrelated to the treatment of bronchoconstriction.

Patent application US2010/0057154, entitled Device and method for thetransdermal stimulation of a nerve of the human body, to DIETRICH etal., discloses a non-invasive transcutaneous/transdermal method forstimulating the vagus nerve, at an anatomical location where the vagusnerve has paths in the skin of the external auditory canal. Theirnon-invasive method involves performing electrical stimulation at thatlocation, using surface stimulators that are similar to those used forperipheral nerve and muscle stimulation for treatment of pain(transdermal electrical nerve stimulation), muscle training (electricalmuscle stimulation) and electroacupuncture of defined meridian points.The method used in that application is similar to the ones used in U.S.Pat. No. 4,319,584, entitled Electrical pulse acupressure system, toMcCALL, for electroacupuncture; U.S. Pat. No. 5,514,175 entitledAuricular electrical stimulator, to KIM et al., for the treatment ofpain; and U.S. Pat. No. 4,966,164, entitled Combined sound generatingdevice and electrical acupuncture device and method for using the same,to COLSEN et al., for combined sound/electroacupuncture. A relatedapplication is US2006/0122675, entitled Stimulator for auricular branchof vagus nerve, to LIBBUS et al. Similarly, U.S. Pat. No. 7,386,347,entitled Electric stimulator for alpha-wave derivation, to CHUNG et al.,described electrical stimulation of the vagus nerve at the ear. Patentapplication US2008/0288016, entitled Systems and Methods for StimulatingNeural Targets, to AMURTHUR et al., also discloses electricalstimulation of the vagus nerve at the ear. However, none of thedisclosures in these patents or patent applications for electricalstimulation of the vagus nerve at the ear are used to treatbronchoconstriction.

Embodiments of the present invention may differ with regard to thenumber of electrodes that are used, the distance between electrodes, andwhether disk or ring electrodes are used. In preferred embodiments ofthe method, one selects the electrode configuration for individualpatients, in such a way as to optimally focus electric fields andcurrents onto the selected nerve, without generating excessive currentson the surface of the skin. This tradeoff between focality and surfacecurrents is described by DATTA et al. [Abhishek DATTA, Maged Elwassif,Fortunato Battaglia and Marom Bikson. Transcranial current stimulationfocality using disc and ring electrode configurations: FEM analysis. J.Neural Eng. 5 (2008): 163-174]. Although DATTA et al. are addressing theselection of electrode configuration specifically for transcranialcurrent stimulation, the principles that they describe are applicable toperipheral nerves as well [RATTAY F. Analysis of models forextracellular fiber stimulation. IEEE Trans. Biomed. Eng. 36 (1989):676-682].

Considering that the nerve stimulating device 301 in FIG. 2A and thenerve stimulating device 302 in FIG. 2B both control the shape ofelectrical impulses, their functions are analogous, except that onestimulates nerves via a pulse of a magnetic field, and the otherstimulates nerves via an electrical pulse applied through surfaceelectrodes. Accordingly, general features recited for the nervestimulating device 301 apply as well to the latter stimulating device302 and will not be repeated here. The preferred parameters for eachnerve stimulating device are those that produce the desired therapeuticeffects.

A preferred embodiment of an electrode-based stimulator is shown in FIG.7A. A cross-sectional view of the stimulator along its long axis isshown in FIG. 7B. As shown, the stimulator (730) comprises two heads(731) and a body (732) that joins them. Each head (731) contains astimulating electrode. The body of the stimulator (732) contains theelectronic components and battery (not shown) that are used to generatethe signals that drive the electrodes, which are located behind theinsulating board (733) that is shown in FIG. 7B. However, in otherembodiments of the invention, the electronic components that generatethe signals that are applied to the electrodes may be separate, butconnected to the electrode head (731) using wires. Furthermore, otherembodiments of the invention may contain a single such head or more thantwo heads.

Heads of the stimulator (731) are applied to a surface of the patient'sbody, during which time the stimulator may be held in place by straps orframes (not shown), or the stimulator may be held against the patient'sbody by hand. In either case, the level of stimulation power may beadjusted with a wheel (734) that also serves as an on/off switch. Alight (735) is illuminated when power is being supplied to thestimulator. An optional cap may be provided to cover each of thestimulator heads (731), to protect the device when not in use, to avoidaccidental stimulation, and to prevent material within the head fromleaking or drying. Thus, in this embodiment of the invention, mechanicaland electronic components of the stimulator (impulse generator, controlunit, and power source) are compact, portable, and simple to operate.

Details of one embodiment of the stimulator head are shown in FIGS. 7Cand 7D. The electrode head may be assembled from a disc withoutfenestration (743), or alternatively from a snap-on cap that serves as atambour for a dielectric or conducting membrane, or alternatively thehead may have a solid fenestrated head-cup. The electrode may also be ascrew (745). The preferred embodiment of the disc (743) is a solid,ordinarily uniformly conducting disc (e.g., metal such as stainlesssteel), which is possibly flexible in some embodiments. An alternateembodiment of the disc is a non-conducting (e.g., plastic) aperturescreen that permits electrical current to pass through its apertures,e.g., through an array of apertures (fenestration). The electrode (745,also 340 in FIG. 2B) seen in each stimulator head may have the shape ofa screw that is flattened on its tip. Pointing of the tip would make theelectrode more of a point source, such that the equations for theelectrical potential may have a solution corresponding more closely to afar-field approximation. Rounding of the electrode surface or making thesurface with another shape will likewise affect the boundary conditionsthat determine the electric field. Completed assembly of the stimulatorhead is shown in FIG. 7D, which also shows how the head is attached tothe body of the stimulator (747).

If a membrane is used, it ordinarily serves as the interface shown as351 in FIG. 2B. For example, the membrane may be made of a dielectric(non-conducting) material, such as a thin sheet of Mylar(biaxially-oriented polyethylene terephthalate, also known as BoPET). Inother embodiments, it may be made of conducting material, such as asheet of Tecophlic material from Lubrizol Corporation, 29400 LakelandBoulevard, Wickliffe, Ohio 44092. In one embodiment, apertures of thedisc may be open, or they may be plugged with conducting material, forexample, KM10T hydrogel from Katecho Inc., 4020 Gannett Ave., Des MoinesIowa 50321. If the apertures are so-plugged, and the membrane is made ofconducting material, the membrane becomes optional, and the plug servesas the interface 351 shown in FIG. 2B.

The head-cup (744) is filled with conducting material (350 in FIG. 2B),for example, SIGNAGEL Electrode Gel from Parker Laboratories, Inc., 286Eldridge Rd., Fairfield N.J. 07004. The head-cup (744) and body of thestimulator are made of a non-conducting material, such as acrylonitrilebutadiene styrene. The depth of the head-cup from its top surface to theelectrode may be between one and six centimeters. The head-cup may havea different curvature than what is shown in FIG. 7, or it may be tubularor conical or have some other inner surface geometry that will affectthe Neumann boundary conditions that determine the electric fieldstrength.

If an outer membrane is used and is made of conducting materials, andthe disc (743) in FIG. 7C is made of solid conducting materials such asstainless steel, then the membrane becomes optional, in which case thedisc may serve as the interface 351 shown in FIG. 2B. Thus, anembodiment without the membrane is shown in FIGS. 7C and 7D. FIG. 7Eshows that this version of the device comprises a solid (but possiblyflexible in some embodiments) conducting disc that cannot absorb fluid,the non-conducting stimulator head (744) into or onto which the disc isplaced, and the electrode (745), which is also a screw. It is understoodthat the disc (743) may have an anisotropic material or electricalstructure, for example, wherein a disc of stainless steel has a grain,such that the grain of the disc should be rotated about its location onthe stimulator head, in order to achieve optimal electrical stimulationof the patient. As seen in FIG. 7D, these items are assembled to becomea sealed stimulator head that is attached to the body of the stimulator(747). The disc (743) may screw into the stimulator head (744), it maybe attached to the head with adhesive, or it may be attached by othermethods that are known in the art. The chamber of the stimulatorhead-cup is filled with a conducting gel, fluid, or paste, and becausethe disc (743) and electrode (745) are tightly sealed against thestimulator head-cup (744), the conducting material within the stimulatorhead cannot leak out.

In some embodiments, the interface and/or its underlying mechanicalsupport comprise materials that will also provide a substantial orcomplete seal of the interior of the device. This inhibits any leakageof conducting material, such as gel, from the interior of the device andalso inhibits any fluids from entering the device. In addition, thisfeature allows the user to easily clean the outer surface of the device(e.g., with isopropyl alcohol or similar disinfectant), avoidingpotential contamination during subsequent uses of the device.

In some embodiments, the interface comprises a fluid permeable materialthat allows for passage of current through the permeable portions of thematerial. In these embodiments, a conductive medium (such as a gel) ispreferably situated between the electrode(s) and the permeableinterface. The conductive medium provides a conductive pathway forelectrons to pass through the permeable interface to the outer surfaceof the interface and to the patient's skin.

In other embodiments of the present invention, the interface (351 inFIG. 2B) is made from a very thin material with a high dielectricconstant, such as material used to make capacitors. For example, it maybe Mylar having a submicron thickness (preferably in the range 0.5 to1.5 microns) having a dielectric constant of about 3. Because one sideof Mylar is slick, and the other side is microscopically rough, thepresent invention contemplates two different configurations: one inwhich the slick side is oriented towards the patient's skin, and theother in which the rough side is so-oriented. Thus, at stimulationFourier frequencies of several kilohertz or greater, the dielectricinterface will capacitively couple the signal through itself, because itwill have an impedance comparable to that of the skin. Thus, thedielectric interface will isolate the stimulator's electrode from thetissue, yet allow current to pass. In one embodiment of the presentinvention, non-invasive electrical stimulation of a nerve isaccomplished essentially substantially capacitively, which reduces theamount of ohmic stimulation, thereby reducing the sensation the patientfeels on the tissue surface. This would correspond to a situation, forexample, in which at least 30%, preferably at least 50%, of the energystimulating the nerve comes from capacitive coupling through thestimulator interface, rather than from ohmic coupling. In other words, asubstantial portion (e.g., 50%) of the voltage drop is across thedielectric interface, while the remaining portion is through the tissue.

The selection of the material for the dielectric constant involves atleast two important variables: (1) the thickness of the interface; and(2) the dielectric constant of the material. The thinner the interfaceand/or the higher the dielectric constant of the material, the lower thevoltage drop across the dielectric interface (and thus the lower thedriving voltage required). For example, with Mylar, the thickness couldbe about 0.5 to 5 microns (preferably about 1 micron) with a dielectricconstant of about 3. For a piezoelectric material like barium titanateor PZT (lead zirconate titanate), the thickness could be about 100-400microns (preferably about 200 microns or 0.2 mm) because the dielectricconstant is >1000.

One of the novelties of the embodiment that is a non-invasive capacitivestimulator (hereinafter referred to more generally as a capacitiveelectrode) arises in that it uses a low voltage (generally less than 100volt) power source, which is made possible by the use of a suitablestimulation waveform, such as the waveform that is disclosed herein(FIG. 2). In addition, the capacitive electrode allows for the use of aninterface that provides a more adequate seal of the interior of thedevice. The capacitive electrode may be used by applying a small amountof conductive material (e.g., conductive gel as described above) to itsouter surface. In some embodiments, it may also be used by contactingdry skin, thereby avoiding the inconvenience of applying an electrodegel, paste, or other electrolytic material to the patient's skin andavoiding the problems associated with the drying of electrode pastes andgels. Such a dry electrode would be particularly suitable for use with apatient who exhibits dermatitis after the electrode gel is placed incontact with the skin [Ralph J. COSKEY. Contact dermatitis caused by ECGelectrode jelly. Arch Dermatol 113(1977): 839-840]. The capacitiveelectrode may also be used to contact skin that has been wetted (e.g.,with tap water or a more conventional electrolyte material) to make theelectrode-skin contact (here the dielectric constant) more uniform [A LALEXELONESCU, G Barbero, F C M Freire, and R Merletti. Effect ofcomposition on the dielectric properties of hydrogels for biomedicalapplications. Physiol. Meas. 31 (2010) S169-S182].

As described below, capacitive biomedical electrodes are known in theart, but when used to stimulate a nerve noninvasively, a high voltagepower supply is currently used to perform the stimulation. Otherwise,prior use of capacitive biomedical electrodes has been limited toinvasive, implanted applications; to non-invasive applications thatinvolve monitoring or recording of a signal, but not stimulation oftissue; to non-invasive applications that involve the stimulation ofsomething other than a nerve (e.g., tumor); or as the dispersiveelectrode in electrosurgery.

Evidence of a long-felt but unsolved need, and evidence of failure ofothers to solve the problem that is solved by the this embodiment of thepresent invention (low-voltage, non-invasive capacitive stimulation of anerve), is provided by KELLER and Kuhn, who review the previoushigh-voltage capacitive stimulating electrode of GEDDES et al and writethat “Capacitive stimulation would be a preferred way of activatingmuscle nerves and fibers, when the inherent danger of high voltagebreakdowns of the dielectric material can be eliminated. Goal of futureresearch could be the development of improved and ultra-thin dielectricfoils, such that the high stimulation voltage can be lowered.” [L. A.GEDDES, M. Hinds, and K. S. Foster. Stimulation with capacitorelectrodes. Medical and Biological Engineering and Computing 25(1987):359-360; Thierry KELLER and Andreas Kuhn. Electrodes for transcutaneous(surface) electrical stimulation. Journal of Automatic Control,University of Belgrade 18(2, 2008):35-45, on page 39]. It is understoodthat in the United States, according to the 2005 National ElectricalCode, high voltage is any voltage over 600 volts. U.S. Pat. No.3,077,884, entitled Electro-physiotherapy apparatus, to BARTROW et al,U.S. Pat. No. 4,144,893, entitled Neuromuscular therapy device, toHICKEY and U.S. Pat. No. 7,933,648, entitled High voltage transcutaneouselectrical stimulation device and method, to TANRISEVER, also describehigh voltage capacitive stimulation electrodes. U.S. Pat. No. 7,904,180,entitled Capacitive medical electrode, to JUOLA et al, describes acapacitive electrode that includes transcutaneous nerve stimulation asone intended application, but that patent does not describe stimulationvoltages or stimulation waveforms and frequencies that are to be usedfor the transcutaneous stimulation. U.S. Pat. No. 7,715,921, entitledElectrodes for applying an electric field in-vivo over an extendedperiod of time, to PALTI, and U.S. Pat. No. 7,805,201, entitled Treatinga tumor or the like with an electric field, to PALTI, also describecapacitive stimulation electrodes, but they are intended for thetreatment of tumors, do not disclose uses involving nerves, and teachstimulation frequencies in the range of 50 kHz to about 500 kHz.

This embodiment of the present invention uses a different method tolower the high stimulation voltage than developing ultra-thin dielectricfoils, namely, to use a suitable stimulation waveform, such as thewaveform that is disclosed herein (FIG. 2). That waveform hassignificant Fourier components at higher frequencies than waveforms usedfor transcutaneous nerve stimulation as currently practiced. Thus, oneof ordinary skill in the art would not have combined the claimedelements, because transcutaneous nerve stimulation is performed withwaveforms having significant Fourier components only at lowerfrequencies, and noninvasive capacitive nerve stimulation is performedat higher voltages. In fact, the elements in combination do not merelyperform the function that each element performs separately. Thedielectric material alone may be placed in contact with the skin inorder to perform pasteless or dry stimulation, with a more uniformcurrent density than is associated with ohmic stimulation, albeit withhigh stimulation voltages [L. A. GEDDES, M. Hinds, and K. S. Foster.Stimulation with capacitor electrodes. Medical and BiologicalEngineering and Computing 25(1987): 359-360; Yongmin KIM, H. GunterZieber, and Frank A. Yang. Uniformity of current density understimulating electrodes. Critical Reviews in Biomedical Engineering17(1990, 6): 585-619]. With regard to the waveform element, a waveformthat has significant Fourier components at higher frequencies thanwaveforms currently used for transcutaneous nerve stimulation may beused to selectively stimulate a deep nerve and avoid stimulating othernerves, as disclosed herein for both noncapacitive and capacitiveelectrodes. But it is the combination of the two elements (dielectricinterface and waveform) that makes it possible to stimulate a nervecapacitively without using the high stimulation voltage as is currentlypracticed.

Another embodiment of the electrode-based stimulator is shown in FIG. 8,showing a device in which electrically conducting material is dispensedfrom the device to the patient's skin. In this embodiment, the interface(351 in FIG. 2B) is the conducting material itself. FIGS. 8A and 8Brespectively provide top and bottom views of the outer surface of theelectrical stimulator 50. FIG. 8C provides a bottom view of thestimulator 50, after sectioning along its long axis to reveal the insideof the stimulator.

FIGS. 8A and 8C show a mesh 51 with openings that permit a conductinggel to pass from inside of the stimulator to the surface of thepatient's skin at the position of nerve or tissue stimulation. Thus, themesh with openings 51 is the part of the stimulator that is applied tothe skin of the patient, through which conducting material may bedispensed. In any given stimulator, the distance between the two meshopenings 51 in FIG. 8A is constant, but it is understood that differentstimulators may be built with different inter-mesh distances, in orderto accommodate the anatomy and physiology of individual patients.Alternatively, the inter-mesh distance may be made variable as in theeyepieces of a pair of binoculars. A covering cap (not shown) is alsoprovided to fit snugly over the top of the stimulator housing and themesh openings 51, in order to keep the housing's conducting medium fromleaking or drying when the device is not in use.

FIGS. 8B and 8C show the bottom of the self-contained stimulator 50. Anon/off switch 52 is attached through a port 54, and a power-levelcontroller 53 is attached through another port 54. The switch isconnected to a battery power source (320 in FIG. 2B), and thepower-level controller is attached to the control unit (330 in FIG. 2B)of the device. The power source battery and power-level controller, aswell as the impulse generator (310 in FIG. 2B) are located (but notshown) in the rear compartment 55 of the housing of the stimulator 50.

Individual wires (not shown) connect the impulse generator (310 in FIG.2B) to the stimulator's electrodes 56. The two electrodes 56 are shownhere to be elliptical metal discs situated between the head compartment57 and rear compartment 55 of the stimulator 50. A partition 58separates each of the two head compartments 57 from one another and fromthe single rear compartment 55. Each partition 58 also holds itscorresponding electrode in place. However, each electrode 56 may beremoved to add electrically conducting gel (350 in FIG. 2B) to each headcompartment 57. An optional non-conducting variable-aperture irisdiaphragm may be placed in front of each of the electrodes within thehead compartment 57, in order to vary the effective surface area of eachof the electrodes. Each partition 58 may also slide towards the head ofthe device in order to dispense conducting gel through the meshapertures 51. The position of each partition 58 therefore determines thedistance 59 between its electrode 56 and mesh openings 51, which isvariable in order to obtain the optimally uniform current densitythrough the mesh openings 51. The outside housing of the stimulator 50,as well as each head compartment 57 housing and its partition 58, aremade of electrically insulating material, such as acrylonitrilebutadiene styrene, so that the two head compartments are electricallyinsulated from one another. Although the embodiment in FIG. 8 is shownto be a non-capacitive stimulator, it is understood that it may beconverted into a capacitive stimulator by replacing the mesh openings 51with a dielectric material, such as a sheet of Mylar, or by covering themesh openings 51 with a sheet of such dielectric material.

In preferred embodiments of the electrode-based stimulator shown in FIG.2B, electrodes are made of a metal, such as stainless steel, platinum,or a platinum-iridium alloy. However, in other embodiments, theelectrodes may have many other sizes and shapes, and they may be made ofother materials [Thierry KELLER and Andreas Kuhn. Electrodes fortranscutaneous (surface) electrical stimulation. Journal of AutomaticControl, University of Belgrade, 18(2, 2008):35-45; G. M. LYONS, G. E.Leane, M. Clarke-Moloney, J. V. O'Brien, P. A. Grace. An investigationof the effect of electrode size and electrode location on comfort duringstimulation of the gastrocnemius muscle. Medical Engineering & Physics26 (2004) 873-878; Bonnie J. FORRESTER and Jerrold S. Petrofsky. Effectof Electrode Size, Shape, and Placement During Electrical Stimulation.The Journal of Applied Research 4, (2, 2004): 346-354; Gad ALON, GideonKantor and Henry S. Ho. Effects of Electrode Size on Basic ExcitatoryResponses and on Selected Stimulus Parameters. Journal of Orthopaedicand Sports Physical Therapy. 20(1, 1994):29-35].

For example, there may be more than two electrodes; the electrodes maycomprise multiple concentric rings; and the electrodes may bedisc-shaped or have a non-planar geometry. They may be made of othermetals or resistive materials such as silicon-rubber impregnated withcarbon that have different conductive properties [Stuart F. COGAN.Neural Stimulation and Recording Electrodes. Annu. Rev. Biomed. Eng.2008. 10:275-309; Michael F. NOLAN. Conductive differences in electrodesused with transcutaneous electrical nerve stimulation devices. PhysicalTherapy 71(1991):746-751].

Although the electrode may consist of arrays of conducting material, theembodiments shown in FIGS. 7 and 8 avoid the complexity and expense ofarray or grid electrodes [Ana POPOVIC-BIJELIC, Goran Bijelic, NikolaJorgovanovic, Dubravka Bojanic, Mirjana B. Popovic, and Dejan B.Popovic. Multi-Field Surface Electrode for Selective ElectricalStimulation. Artificial Organs 29 (6, 2005):448-452; Dejan B. POPOVICand Mirjana B. Popovic. Automatic determination of the optimal shape ofa surface electrode: Selective stimulation. Journal of NeuroscienceMethods 178 (2009) 174-181; Thierry KELLER, Marc Lawrence, Andreas Kuhn,and Manfred Morari. New Multi-Channel Transcutaneous ElectricalStimulation Technology for Rehabilitation. Proceedings of the 28th IEEEEMBS Annual International Conference New York City, USA, Aug. 30-Sep. 3,2006 (WeC14.5): 194-197]. This is because the designs shown in FIGS. 7and 8 provide a uniform surface current density, which would otherwisebe a potential advantage of electrode arrays, and which is a trait thatis not shared by most electrode designs [Kenneth R. BRENNEN. TheCharacterization of Transcutaneous Stimulating Electrodes. IEEETransactions on Biomedical Engineering BME-23 (4, 1976): 337-340; AndreiPATRICIU, Ken Yoshida, Johannes J. Struijk, Tim P. DeMonte, Michael L.G. Joy, and Hans Stødkilde-Jørgensen. Current Density Imaging andElectrically Induced Skin Burns Under Surface Electrodes. IEEETransactions on Biomedical Engineering 52 (12, 2005): 2024-2031; R. H.GEUZE. Two methods for homogeneous field defibrillation and stimulation.Med. and Biol. Eng. and Comput. 21(1983), 518-520; J. PETROFSKY, E.Schwab, M. Cuneo, J. George, J. Kim, A. Almalty, D. Lawson, E. Johnsonand W. Remigo. Current distribution under electrodes in relation tostimulation current and skin blood flow: are modern electrodes reallyproviding the current distribution during stimulation we believe theyare? Journal of Medical Engineering and Technology 30 (6, 2006):368-381; Russell G. MAUS, Erin M. McDonald, and R. Mark Wightman.Imaging of Nonuniform Current Density at Microelectrodes byElectrogenerated Chemiluminescence. Anal. Chem. 71(1999): 4944-4950]. Infact, patients found the design shown in FIGS. 7 and 8 to be lesspainful in a direct comparison with a commercially availablegrid-pattern electrode [UltraStim grid-pattern electrode, AxelggardManufacturing Company, 520 Industrial Way, Fallbrook Calif., 2011]. Theembodiment of the electrode that uses capacitive coupling isparticularly suited to the generation of uniform stimulation currents[Yongmin KIM, H. Gunter Zieber, and Frank A. Yang. Uniformity of currentdensity under stimulating electrodes. Critical Reviews in BiomedicalEngineering 17(1990, 6): 585-619].

The electrode-based stimulator designs shown in FIGS. 7 and 8 situatethe electrode remotely from the surface of the skin within a chamber,with conducting material placed in the chamber between the skin andelectrode. Such a chamber design had been used prior to the availabilityof flexible, flat, disposable electrodes [U.S. Pat. No. 3,659,614,entitled Adjustable headband carrying electrodes for electricallystimulating the facial and mandibular nerves, to Jankelson; US3590810,entitled Biomedical body electode, to Kopecky; U.S. Pat. No. 3,279,468,entitled Electrotherapeutic facial mask apparatus, to Le Vine; U.S. Pat.No. 6,757,556, entitled Electrode sensor, to Gopinathan et al; U.S. Pat.No. 4,383,529, entitled Iontophoretic electrode device, method and gelinsert, to Webster; U.S. Pat. No. 4,220,159, entitled Electrode, toFrancis et al. U.S. Pat. No. 3,862,633, U.S. Pat. No. 4,182,346, andU.S. Pat. No. 3,973,557, entitled Electrode, to Allison et al; U.S. Pat.No. 4,215,696, entitled Biomedical electrode with pressurized skincontact, to Bremer et al; and U.S. Pat. No. 4,166,457, entitled Fluidself-sealing bioelectrode, to Jacobsen et al.] The stimulator designsshown in FIGS. 7 and 8 are also self-contained units, housing theelectrodes, signal electronics, and power supply. Portable stimulatorsare also known in the art, for example, U.S. Pat. No. 7,171,266,entitled Electro-acupuncture device with stimulation electrode assembly,to Gruzdowich. One of the novelties of the designs shown in FIGS. 7 and8 is that the stimulator, along with a correspondingly suitablestimulation waveform, shapes the electric field, producing a selectivephysiological response by stimulating that nerve, but avoidingsubstantial stimulation of nerves and tissue other than the targetnerve, particularly avoiding the stimulation of nerves that producepain. The shaping of the electric field is described in terms of thecorresponding field equations in commonly assigned applicationUS20110230938 (application Ser. No. 13/075,746) entitled Devices andmethods for non-invasive electrical stimulation and their use for vagalnerve stimulation on the neck of a patient, to SIMON et al., which ishereby incorporated by reference.

In one embodiment, the magnetic stimulator coil 341 in FIG. 2A has abody that is similar to the electrode-based stimulator shown in FIG. 8C.To compare the electrode-based stimulator with the magnetic stimulator,refer to FIG. 8D, which shows the magnetic stimulator 530 sectionedalong its long axis to reveal its inner structure. As described below,it reduces the volume of conducting material that must surround atoroidal coil, by using two toroids, side-by-side, and passingelectrical current through the two toroidal coils in oppositedirections. In this configuration, the induced electrical current willflow from the lumen of one toroid, through the tissue and back throughthe lumen of the other, completing the circuit within the toroids'conducting medium. Thus, minimal space for the conducting medium isrequired around the outside of the toroids at positions near from thegap between the pair of coils. An additional advantage of using twotoroids in this configuration is that this design will greatly increasethe magnitude of the electric field gradient between them, which iscrucial for exciting long, straight axons such as the vagus nerve andcertain peripheral nerves.

As seen in FIG. 8D, a mesh 531 has openings that permit a conducting gel(within 351 in FIG. 2A) to pass from the inside of the stimulator to thesurface of the patient's skin at the location of nerve or tissuestimulation. Thus, the mesh with openings 531 is the part of themagnetic stimulator that is applied to the skin of the patient.

FIG. 8D also shows openings at the opposite end of the magneticstimulator 530. One of the openings is an electronics port 532 throughwhich wires pass from the stimulator coil(s) to the impulse generator(310 in FIG. 2A). The second opening is a conducting gel port 533through which conducting gel (351 in FIG. 2A) may be introduced into themagnetic stimulator 530 and through which a screw-driven piston arm maybe introduced to dispense conducting gel through the mesh 531. The gelitself is contained within cylindrical-shaped but interconnectedconducting medium chambers 534 that are shown in FIG. 8D. The depth ofthe conducting medium chambers 534, which is approximately the height ofthe long axis of the stimulator, affects the magnitude of the electricfields and currents that are induced by the magnetic stimulator device[Rafael CARBUNARU and Dominique M. Durand. Toroidal coil models fortranscutaneous magnetic stimulation of nerves. IEEE Transactions onBiomedical Engineering. 48 (4, 2001): 434-441].

FIG. 8D also show the coils of wire 535 that are wound around toroidalcores 536, consisting of high-permeability material (e.g., Supermendur).Lead wires (not shown) for the coils 535 pass from the stimulatorcoil(s) to the impulse generator (310 in FIG. 2A) via the electronicsport 532. Different circuit configurations are contemplated. If separatelead wires for each of the coils 535 connect to the impulse generator(i.e., parallel connection), and if the pair of coils are wound with thesame handedness around the cores, then the design is for current to passin opposite directions through the two coils. On the other hand, if thecoils are wound with opposite handedness around the cores, then the leadwires for the coils may be connected in series to the impulse generator,or if they are connected to the impulse generator in parallel, then thedesign is for current to pass in the same direction through both coils.

As also seen in FIG. 8D, the coils 535 and cores 536 around which theyare wound are mounted as close as practical to the corresponding mesh531 with openings through which conducting gel passes to the surface ofthe patient's skin. As shown, each coil and the core around which it iswound is mounted in its own housing 537, the function of which is toprovide mechanical support to the coil and core, as well as toelectrically insulate a coil from its neighboring coil. With thisdesign, induced current will flow from the lumen of one toroid, throughthe tissue and back through the lumen of the other, completing thecircuit within the toroids' conducting medium. A difference between thestructure of the electrode-based stimulator shown in FIG. 8C and themagnetic stimulator shown in FIG. 5D is that the conducting gel ismaintained within the chambers 57 of the electrode-based stimulator,which is generally closed on the back side of the chamber because of thepresence of the electrode 56; but in the magnetic stimulator, the holeof each toroidal core and winding is open, permitting the conducting gelto enter the interconnected chambers 534.

Application of the Stimulators to the Neck of the Patient

Selected nerve fibers are stimulated in different embodiments of methodsthat make use of the disclosed electrical stimulation devices, includingstimulation of the vagus nerve at a location in the patient's neck. Atthat location, the vagus nerve is situated within the carotid sheath,near the carotid artery and the interior jugular vein. The carotidsheath is located at the lateral boundary of the retopharyngeal space oneach side of the neck and deep to the sternocleidomastoid muscle. Theleft vagus nerve is sometimes selected for stimulation becausestimulation of the right vagus nerve may produce undesired effects onthe heart, but depending on the application, the right vagus nerve orboth right and left vagus nerves may be stimulated instead.

The three major structures within the carotid sheath are the commoncarotid artery, the internal jugular vein and the vagus nerve. Thecarotid artery lies medial to the internal jugular vein, and the vagusnerve is situated posteriorly between the two vessels. Typically, thelocation of the carotid sheath or interior jugular vein in a patient(and therefore the location of the vagus nerve) will be ascertained inany manner known in the art, e.g., by feel or ultrasound imaging.Proceeding from the skin of the neck above the sternocleidomastoidmuscle to the vagus nerve, a line may pass successively through thesternocleidomastoid muscle, the carotid sheath and the internal jugularvein, unless the position on the skin is immediately to either side ofthe external jugular vein. In the latter case, the line may passsuccessively through only the sternocleidomastoid muscle and the carotidsheath before encountering the vagus nerve, missing the interior jugularvein. Accordingly, a point on the neck adjacent to the external jugularvein might be preferred for non-invasive stimulation of the vagus nerve.The magnetic stimulator coil may be centered on such a point, at thelevel of about the fifth to sixth cervical vertebra.

FIG. 9 illustrates use of the devices shown in FIGS. 2, 6, 7, and 8 tostimulate the vagus nerve at that location in the neck, in which thestimulator device 50 or 530 in FIG. 8 is shown to be applied to thetarget location on the patient's neck as described above. For reference,locations of the following vertebrae are also shown: first cervicalvertebra 71, the fifth cervical vertebra 75, the sixth cervical vertebra76, and the seventh cervical vertebra 77.

FIG. 10 provides a more detailed view of use of the electricalstimulator, when positioned to stimulate the vagus nerve at the necklocation that is indicated in FIG. 9. As shown, the stimulator 50 inFIG. 8 touches the neck indirectly, by making electrical contact throughconducting gel 29 (or other conducting material) which may be isdispensed through mesh openings (identified as 51 in FIG. 8) of thestimulator or applied as an electrode gel or paste. The layer ofconducting gel 29 in FIG. 10 is shown to connect the device to thepatient's skin, but it is understood that the actual location of the gellayer(s) may be generally determined by the location of mesh 51 shown inFIG. 8. Furthermore, it is understood that for other embodiments of theinvention, the conductive head of the device may not necessitate the useof additional conductive material being applied to the skin.

The vagus nerve 60 is identified in FIG. 10, along with the carotidsheath 61 that is identified there in bold peripheral outline. Thecarotid sheath encloses not only the vagus nerve, but also the internaljugular vein 62 and the common carotid artery 63. Features that may beidentified near the surface of the neck include the external jugularvein 64 and the sternocleidomastoid muscle 65. Additional organs in thevicinity of the vagus nerve include the trachea 66, thyroid gland 67,esophagus 68, scalenus anterior muscle 69, and scalenus medius muscle70. The sixth cervical vertebra 76 is also shown in FIG. 10, with bonystructure indicated by hatching marks.

Methods of treating a patient comprise stimulating the vagus nerve asindicated in FIGS. 9 and 10, using the electrical stimulation devicesthat are disclosed herein. The position and angular orientation of thedevice are adjusted about that location until the patient perceivesstimulation when current is passed through the stimulator electrodes.The applied current is increased gradually, first to a level wherein thepatient feels sensation from the stimulation. The power is thenincreased, but is set to a level that is less than one at which thepatient first indicates any discomfort. Straps, harnesses, or frames areused to maintain the stimulator in position (not shown in FIG. 9 or 10).The stimulator signal may have a frequency and other parameters that areselected to produce a therapeutic result in the patient. Stimulationparameters for each patient are adjusted on an individualized basis.Ordinarily, the amplitude of the stimulation signal is set to themaximum that is comfortable for the patient, and then the otherstimulation parameters are adjusted.

The stimulation is then performed with a sinusoidal burst waveform likethat shown in FIG. 2. The pattern of a burst followed by silentinter-burst period repeats itself with a period of T. For example, thesinusoidal period r may be 200 microseconds; the number of pulses perburst may be N=5; and the whole pattern of burst followed by silentinter-burst period may have a period of T=40000 microseconds, which iscomparable to 25 Hz stimulation. More generally, there may be 1 to 20pulses per burst, preferably five pulses. Each pulse within a burst hasa duration of 1 to 1000 microseconds, preferably 200 microseconds. Aburst followed by a silent inter-burst interval repeats at 1 to 5000bursts per second (bps), preferably at 5-50 bps, and even morepreferably 10-25 bps stimulation (10-25 Hz). The preferred shape of eachpulse is a full sinusoidal wave, although triangular or other shapes maybe used as well. For some patients, a single stimulation session of 90to 120 seconds may be performed (acute situation). For other patients,the stimulation may be performed for 30 minutes and the treatment isperformed once a week for 12 weeks or longer (chronic situation).However, it is understood that parameters of the stimulation protocolmay be varied in response to heterogeneity in the pathophysiology ofpatients.

In other embodiments of the invention, pairing of vagus nervestimulation may be with a time-varying sensory stimulation. The pairedsensory stimulation may be bright light, sound, tactile stimulation, orelectrical stimulation of the tongue to simulate odor/taste, e.g.,pulsating with the same frequency as the vagus nerve electricalstimulation. The rationale for paired sensory stimulation is the same assimultaneous, paired stimulation of both left and right vagus nerves,namely, that the pair of signals interacting with one another in thebrain may result in the formation of larger and more coherent neuralensembles than the neural ensembles associated with the individualsignals, thereby enhancing the therapeutic effect. For example, thehypothalamus is well known to be responsive to the presence of brightlight, so exposing the patient to bright light that is fluctuating withthe same stimulation frequency as the vagus nerve (or a multiple of thatfrequency) may be performed in an attempt to enhance the role of thehypothalamus in producing the desired therapeutic effect. Such pairedstimulation does not necessarily rely upon neuronal plasticity and is inthat sense different from other reports of paired stimulation [Navzer D.ENGINEER, Jonathan R. Riley, Jonathan D. Seale, Will A. Vrana, Jai A.Shetake, Sindhu P. Sudanagunta, Michael S. Borland and Michael P.Kilgard. Reversing pathological neural activity using targetedplasticity. Nature 470(7332, 2011):101-4].

The individualized selection of parameters for the nerve stimulationprotocol may based on trial and error in order to obtain a beneficialresponse without the sensation of pain or muscle twitches. Ordinarily,the amplitude of the stimulation signal is set to the maximum that iscomfortable for the patient, and then the other stimulation parametersare adjusted. Alternatively, the selection of parameter values mayinvolve tuning as understood in control theory, and as described below.It is understood that parameters may also be varied randomly in order tosimulate normal physiological variability, thereby possibly inducing abeneficial response in the patient [Buchman T G. Nonlinear dynamics,complex systems, and the pathobiology of critical illness. Curr OpinCrit Care 10(5, 2004):378-82].

Measurements that are Used to Assess the Extent of a Patient'sBronchoconstriction

Before presenting data in which the disclosed vagus nerve stimulationdevices and methods are applied to patients, as a preliminary, wedescribe measurements that are used to measure bronchoconstriction orbronchodilation. The magnitude of bronchial constriction in a patient istypically evaluated with a measurement referred to as the ForcedExpiratory Volume in one second (FEV1). FEV1 represents the amount ofair that a patient exhales (expressed in liters) in the first second ofa pulmonary function test, which is typically performed with aspirometer. The spirometer compares the FEV1 result to a standard forthe patient, which is based on the predicted value for the patient'sweight, height, sex, age and race. This comparison is then expressed asa percentage of the FEV1 as predicted. Thus, if the volume of airexhaled by a patient in the first second is 60% of the predicted valuebased on the standard, the FEV1 will be expressed in both the actualliters exhaled and as a percentage of predicted (i.e., 60% ofpredicted). In practice, a baseline value of FEV1 is measured, and aftera therapeutic intervention, a second value of FEV1 is measured in orderto ascertain the efficacy of the intervention.

Certain other non-invasive measurements may act as surrogates for themeasurement of FEV1. Those other measurements are particularly usefulfor patients who cannot cooperate to perform measurements made byspirometry, or for situations in which it is not possible to performspirometry. Because those other measurements may be used to generate anon-invasive, continuous signal that indicates the efficacy ofstimulating the selected nerves, they will be discussed below inconnection with their use to provide a feedback signal in the presentinvention, for adjusting the power of the applied impulse, as well asfor adjustment of other stimulation parameters. It should be noted herethat one of them, the interrupter technique (Rint) measures airwayresistance, which according to Poiseuille's Law for laminar air flow, isinversely proportional to the fourth power of the caliber of dilation ofthe bronchi.

The measurement of FEV1 entails first measuring forced expiration volumeas a function of time (the maximum expiratory flow-volume curve, orMEFV, which may be depicted in different ways, e.g., normalized topercentage of vital capacity), then reading the value of the MEFV curveat the one second point. Because a single parameter such as FEV1 cannotcharacterize the entire MEFV curve, it is understood that the MEFV curveitself (or a set of parameters derived from it) more accuratelyrepresents the patient's respiratory status than the FEV1 value alone[Francois HAAS, Kenneth Axen, and John Salazar Schicchi. Use of MaximumExpiratory Flow-Volume Curve Parameters in the Assessment ofExercise-induced Bronchospasm. Chest 1993; 103:64-68]. For example,applicants also report Peak Expiratory Flow (PEF), which is the maximalflow achieved during the maximally forced expiration initiated at fullinspiration, measured in liters per minute. Furthermore, it isunderstood that in order to understand the functional relationshipbetween the magnitude of bronchoconstriction (literally, a reduction inthe average caliber of bronchial lumen) and FEV1, one does so by firstconsidering the relation of each of them to the MEFV curve [Rodney K.LAMBERT and Theodore A. Wilson. Smooth muscle dynamics and maximalexpiratory flow in asthma. J Appl Physiol 99: 1885-1890, 2005].

FEV1 is used as an objective index of airway obstruction in a patient,but for a given value of FEV1, different patients may subjectivelyperceive different amounts of breathlessness corresponding to the workand effort associated with breathing (Work of Breathing, or WOB).Therefore, it is also useful to quantify the patient's subjectivesensation of breathlessness, which is often made as a visual analoguescale (VAS) value [BIJL-HOFLAND I D, Cloosterman S G, Folgering H T,Akkermans R P, van den Hoogen H, van Schayck C P. Measuringbreathlessness during histamine challenge: a simple standardizedprocedure in asthmatic patients. Eur Respir J. 13(1999):955-60; DonaldA. MAHLER. Mechanisms and measurement of dyspnea in chronic obstructivepulmonary disease. Proc Am Thorac Soc 3(2006): 234-238].

As discussed below in connection with a description of Applicant'sclinical data, the present application discloses systems and methods forincreasing a patient's FEV1 in a relatively short period of time.Preferably, an impulse of energy in the form of non-invasive vagus nervestimulation is applied to the patient, which is sufficient to increasethe FEV1 of the patient by a clinically significant amount in a periodof time less than about 6 hours, preferably less than 3 hours and morepreferably less than 90 minutes. In an exemplary embodiment, theclinically significant increase in FEV1 occurs in less than 15 minutes,following ninety seconds of vagus nerve stimulation. A clinicallysignificant amount is defined herein as at least a 12% increase in thepatient's FEV1, versus the FEV1 prior to application of the electricalimpulse.

Method and devices of the present invention are therefore particularlyuseful for providing substantially immediate relief of acute symptomsassociated with bronchial constriction such as asthma attacks, COPDexacerbations and/or anaphylactic reactions. One of the key advantagesof the present invention is the ability to provide almost immediatedilation of the bronchial smooth muscle in patients suffering from acutebronchoconstriction, opening the patient's airways and allowing them tobreathe and more quickly recover from an acute episode (i.e., arelatively rapid onset of symptoms that are typically not prolonged orchronic).

Clinical Data Demonstrating that the Disclosed Stimulation Waveform andDevices Bring about Bronchodilation

As with the animal data that were described above, we first tested thefeasibility of the invention using invasive procedures (percutaneousvagus nerve stimulation), then proceeded to demonstrate the inventionusing totally noninvasive clinical measurements, as follows.

Feasibility of Percutaneous Vagal Nerve Stimulation for the Treatment ofAcute Asthma Exacerbations.

The purpose of this follow-up study was to investigate both the safetyand efficacy of VNS, in humans, delivered through a percutaneouselectrode (pVNS) for the treatment of acute asthma exacerbations. Thestudy subjects were limited to consenting adult emergency department(ED) patients with no further respiratory problems or other pre-existingmedical conditions. Twenty-four ED patients (ages 18-65 years) whofailed to respond to one hour of standard of care (SOC) were treatedwith the percutaneous placement of an electrode near the right carotidsheath (under ultrasound guidance) and then administered 60 minutes ofpVNS and SOC. They were compared with a non-randomized control group of76 subjects who received only SOC.

The primary study outcome measures included adverse events, ForceExpiratory Volume in 1 sec (FEV1), and improvement in perceived Work ofBreathing (WOB) measured on a visual analogue scale. Stimulation for 60minutes showed remarkable improvement in both FEV1 (FIG. 11A) and WOB(FIG. 11B) without serious adverse events, with superiority in thesevalues over SOC at 15, 30, and 60 minutes with p-values of less than0.05 [MINER, J. R., Lewis, L. M., Mosnaim, G. S., Varon, J., Theodoro,D. Hoffman, T. J. Feasibility of percutaneous vagus nerve stimulationfor the treatment of acute asthma exacerbations.” Acad Emerg Med 2012;19: 421-429].

Clinical Studies with Noninvasive Vagus Nerve Stimulation:

Thirty asthma patients were enrolled in an FDA IDE, prospective,multi-centered pilot study to assess safety and efficacy of thedisclosed noninvasive VNS device (the AlphaCore® device). The subjectshad a documented reversible component of bronchoconstriction and wereinstructed to withhold use of an inhaled rescue medication (SABA) untilthey experienced mild to moderate bronchoconstriction. They thenreported to the physician's office for treatment with the AlphaCore, andmonitoring of vital signs, dyspnea and spirometry before, during, andfor 90 min after a single, 90-second treatment.

During the 90-seconds of stimulation most patients reported an immediateimprovement in breathing. This was reflected in a rapid increase in FEV1within one minute of stimulation. FEV1 continued to improve over thefollowing 90 minutes (FIG. 12A). Similar improvements were seen in PeakExpiratory Flow (PEF) with greater than a 10% improvement by 90 min(FIG. 12B). Subjectively, patients reported a significant improvement inbreathing, as reflected in work of breathing (VAS score) improvement ofnearly half in the first few minutes after stimulation, followed bycontinued reduction in the VAS score (FIG. 12C). No adverse events werereported during or after stimulation. There were no significant changesin ECG, heart rate or systolic or diastolic blood pressure (FIGS. 12Dand 12E).

Pilot Clinical Trial in which Patients Take Various Pre- and Post-nVNSMedications.

In practice, the patients who are administered noninvasive vagus nervestimulation (nVNS) in the setting of an emergency department will alsobe administered a variety of medications prior to and after the nVNS. Toascertain whether the use of nVNS as an adjunctive treatment to standardof medicinal care for the relief of acute bronchoconstriction is safeand effective, and whether the results are influenced by the variety ofstandard medications that are taken, the following pilot clinical trialwas performed. After consent was obtained and screening completed, sixsubjects were stimulated two times, 30 minutes apart, for 90 secondseach, using the AlphaCore device as described above. The subjects wereassessed prior to and immediately post the first stimulation and at 15,30, 60, and 90 minutes. Follow-up was also conducted at day 7 and day30. The medications take prior to and after the nVNS are shown as atable in FIG. 13. FIG. 14A summarizes the FEV1 data for these patientsas a function of time following the initial stimulation. The 30 minutemeasurement was taken immediately after the second stimulation. FIG. 14Bsummarizes the Work of Breathing VAS data for these patients as afunction of time. They demonstrate an improvement in lung function and adecrease in the work of breathing, respectively. No clinicallysignificant adverse events requiring unusual treatment were reported,although one patient had a treatable respiratory tract infection uponenrollment, and another patient reported chest tightness at day 4 fromthe date of the stimulation treatment and continued to be treated withmedications.

We therefore conclude from the foregoing preliminary clinical data thatnoninvasive VNS can safely induce significant bronchodilation during anexacerbation of asthma, even in patients with a poor response tostandard pharmacological treatment.

Use of Feedback and Feedforward to Improve Bronchodilation in IndividualPatients

Individualized treatment may be based on the methods that will now bedescribed in connection with the use of control theory to selectstimulation parameters. In brief, the patient's physiological andmedical state are modeled a set of differential equations, for example,as coupled nonlinear oscillators; measurements concerning the patient'sfunction are made preferably using ambulatory measurement sensors;parameters of the equations are estimated using the measurements,including measurement of the patient's function following stimulationwith different parameters that may be used for the stimulation protocol;and a treatment protocol (set of stimulation parameters) is selected innearly real-time that will provide the best outcome and avoid orameliorate the effects of undesired events.

If it is desired to maintain a constant stimulation in the vicinity ofthe vagus nerve (or any other nerve or tissue that is being stimulated),control theory methods may also be employed to modulate the power of thestimulator in order to compensate for patient motion or other mechanismsthat would otherwise give rise to variability in the power ofstimulation. In the case of stimulation of the vagus nerve, suchvariability may be attributable to the patient's breathing, which mayinvolve contraction and associated change in geometry of thesternocleidomastoid muscle that is situated close to the vagus nerve(identified as 65 in FIG. 10). Such modulation may be accomplished usingcontrollers (e.g. PID controllers) that are known in the art of controltheory, as now described.

FIG. 15 is a control theory representation of the disclosed vagus nervestimulation methods, used not only to maintain a constant stimulation,but also used in connection with the selection of stimulation parametersand stimulation protocols as described below. As shown in FIG. 15, thepatient, or the relevant physiological component of the patient, isconsidered to be the “System” that is to be controlled. The “System”(patient) receives input from the “Environment.” For example, in thecase of an asthmatic, the environment would include breathed irritants.If the “System” is defined to be only a particular physiologicalcomponent of the patient, the “Environment” may also be considered toinclude physiological systems of the patient that are not included inthe “System”. Thus, if some physiological component can influence thebehavior of another physiological component of the patient, but not viceversa, the former component could be part of the environment and thelatter could be part of the system. On the other hand, if it is intendedto control the former component to influence the latter component, thenboth components should be considered part of the “System.”

The System also receives input from the “Controller”, which in this casemay comprise the vagus nerve stimulation device, as well as electroniccomponents that may be used to select or set parameters for thestimulation protocol (amplitude, frequency, pulse width, burst number,etc.) or alert the patient as to the need to use or adjust thestimulator (i.e., an alarm). For example, the controller may include thecontrol unit 330 in FIG. 2. Feedback in the schema shown in FIG. 15 ispossible because physiological measurements of the System are made usingsensors. Thus, the values of variables of the system that could bemeasured define the system's state (“the System Output”). As a practicalmatter, only some of those measurements are actually made, and theyrepresent the “Sensed Physiological Input” to the Controller.

The preferred sensors will include ones ordinarily used for ambulatorymonitoring, selected to characterize the heart and lung and themodulation of their function by the autonomic nervous system. Forexample, the sensors may comprise those used in conventional Holter andbedside monitoring applications, for monitoring heart rate andvariability, ECG, respiration depth and rate, core temperature,hydration, blood pressure, brain function, oxygenation, skin impedance,and skin temperature. The sensors may be embedded in garments or placedin sports wristwatches, as currently used in programs that monitor thephysiological status of soldiers [G. A. SHAW, A. M. Siegel, G. Zogbi,and T. P. Opar. Warfighter physiological and environmental monitoring: astudy for the U.S. Army Research Institute in Environmental Medicine andthe Soldier Systems Center. MIT Lincoln Laboratory, Lexington Mass. 1Nov. 2004, pp. 1-141]. The ECG sensors should be adapted to theautomatic extraction and analysis of particular features of the ECG, forexample, indices of P-wave morphology, as well as heart rate variabilityindices of parasympathetic and sympathetic tone. Measurement ofrespiration using noninvasive inductive plethysmography, mercury insilastic strain gauges or impedance pneumography is particularlyadvised, in order to account for the effects of respiration on theheart. A noninvasive accelerometer may also be included among theambulatory sensors, in order to identify motion artifacts. Although someevents such as the onset of atrial fibrillation can be detected from theECG alone or other sensor output, an event marker may also be includedin order for the patient to mark relevant circumstances and sensations.

Detection of the phase of respiration may be performed non-invasively byadhering a thermistor or thermocouple probe to the patient's cheek so asto position the probe at the nasal orifice. Strain gauge signals frombelts strapped around the chest, as well as inductive plethysmographyand impedance pneumography, are also used traditionally tonon-invasively generate a signal that rises and falls as a function ofthe phase of respiration. After digitizing such signals, the phase ofrespiration may be determined using software such as “puka”, which ispart of PhysioToolkit, a large published library of open source softwareand user manuals that are used to process and display a wide range ofphysiological signals [GOLDBERGER A L, Amaral L A N, Glass L, HausdorffJ M, Ivanov P Ch, Mark R G, Mietus J E, Moody G B, Peng C K, Stanley HE. PhysioBank, PhysioToolkit, and PhysioNet: Components of a NewResearch Resource for Complex Physiologic Signals. Circulation 101(23,2000):e215-e220] available from PhysioNet, M.I.T. Room E25-505A, 77Massachusetts Avenue, Cambridge, Mass. 02139]. In one embodiment of thepresent invention, the control unit 330 contains an analog-to-digitalconverter to receive such analog respiratory signals, and software forthe analysis of the digitized respiratory waveform resides within thecontrol unit 330. That software extracts turning points within therespiratory waveform, such as end-expiration and end-inspiration, andforecasts future turning-points, based upon the frequency with whichwaveforms from previous breaths match a partial waveform for the currentbreath. The control unit 330 then controls the impulse generator 310,for example, to stimulate the selected nerve only during a selectedphase of respiration, such as all of inspiration or only the firstsecond of inspiration, or only the expected middle half of inspiration.

It may be therapeutically advantageous to program the control unit 330to control the impulse generator 310 in such a way as to temporallymodulate stimulation by the magnetic stimulator coils or electrodes,depending on the phase of the patient's respiration. In patentapplication JP2008/081479A, entitled Vagus nerve stimulation system, toYOSHIHOTO, a system is also described for keeping the heart rate withinsafe limits. When the heart rate is too high, that system stimulates apatient's vagus nerve, and when the heart rate is too low, that systemtries to achieve stabilization of the heart rate by stimulating theheart itself, rather than use different parameters to stimulate thevagus nerve. In that disclosure, vagal stimulation uses an electrode,which is described as either a surface electrode applied to the bodysurface or an electrode introduced to the vicinity of the vagus nervevia a hypodermic needle. That disclosure is unrelated to the problem ofbronchoconstriction that is addressed herein, but it does considerstimulation during particular phases of the respiratory cycle, for thefollowing reason. Because the vagus nerve is near the phrenic nerve,Yoshihoto indicates that the phrenic nerve will sometimes beelectrically stimulated along with the vagus nerve. The presentapplicants did not experience this problem in the experiments reportedhere, so the problem may be one of a misplaced electrode. In any case,the phrenic nerve controls muscular movement of the diaphragm, soconsequently, stimulation of the phrenic nerve causes the patient tohiccup or experience irregular movement of the diaphragm, or otherwiseexperience discomfort. To minimize the effects of irregular diaphragmmovement, Yoshihoto's system is designed to stimulate the phrenic nerve(and possibly co-stimulate the vagus nerve) only during the inspirationphase of the respiratory cycle and not during expiration. Furthermore,the system is designed to gradually increase and then decrease themagnitude of the electrical stimulation during inspiration (notablyamplitude and stimulus rate) so as to make stimulation of the phrenicnerve and diaphragm gradual. Patent application publicationUS2009/0177252, entitled Synchronization of vagus nerve stimulation withthe cardiac cycle of a patient, to Arthur D. Craig, discloses a methodof treating a medical condition in which the vagus nerve is stimulatedduring a portion of the cardiac cycle and the respiratory cycle. Thatdisclosure pertains to the treatment of a generic medical condition, soit is not specifically directed to the treatment of bronchoconstriction.

In the present application, stimulation of selected nerve fibers duringparticular phases of respiration for the treatment ofbronchoconstriction may be motivated by two additional physiologicalconsiderations. The first is that contraction of bronchial smooth muscleappears to be intrinsically rhythmic. It has been reported thatbronchial smooth muscle contracts preferentially over two phases, duringmid-inspiration and early expiration. When the vagus efferent nerves arerepetitively stimulated with electric pulses, the bronchus constrictedperiodically; tonic constriction is almost absent in the bronchus inresponse to the vagally mediated descending commands [KONDO, Tetsuri,Ichiro Kobayashi, Naoki Hayama, Gen Tazaki, and Yasuyo Ohta.Respiratory-related bronchial rhythmic constrictions in the dog withextracorporeal circulation. J Appl Physiol 88(2000): 2031-2036].Accordingly, a rationale for stimulating the vagus nerve duringparticular phases of the respiratory cycle is that such stimulation maybe used to counteract or inhibit the constriction that occurs naturallyduring those specific phases of respiration. If the counteracting orinhibiting effects occur only after a delay, then the timing of thestimulation pulses must precede the phases of respiration during whichthe contraction would occur, by an interval corresponding to the delay.

Another motivation for stimulating the vagus nerve during particularphases of respiration is that an increase or decrease in the duration ofsubsequent phases of respiration may be produced by applying thestimulation during particular phases of respiration [M. SAMMON, J. R.Romaniuk and E. N. Bruce. Bifurcations of the respiratory patternproduced with phasic vagal stimulation in the rat. J Appl Physiol75(1993): 912-926]. In particular, a narrow window may exist at theexpiratory-inspiratory transition in which it may be possible to inducebursts of inspiratory activity followed by a prolonged breath.Accordingly, if it is therapeutically beneficial to induce deep breaths,those breaths might be induced by stimulating during that time-window.In fact, the physiologically meaningful cycle of stimulation in thiscase is not a single respiratory cycle, but is instead a collectivesequence of respiratory cycles, wherein it makes sense only to speak ofstimulation during particular parts of the sequence.

In some embodiments of the invention, overheating of the magneticstimulator coil may also be minimized by optionally restricting themagnetic stimulation to particular phases of the respiratory cycle,allowing the coil to cool during the other phases of the respiratorycycle. Alternatively, greater peak power may be achieved per respiratorycycle by concentrating all the energy of the magnetic pulses intoselected phases of the respiratory cycle.

In our clinical experiments that were summarized above, the electricalimpulses delivered to the vagus nerve were optimized to have littleeffect on heart rate or blood pressure. However, during asthma or COPDattacks or anaphylactic shock, it is sometimes the case that asignificant increase or decrease in heart rate accompanies airwayconstriction. In cases of unsafe or suboptimal heart rates, theteachings of the present invention permit not only prompt airwaydilation, but also an improved heart rate, to enable subsequent lifesaving measures that otherwise would be ineffective or impossible due tosevere constriction or other physiological effects. Treatment inaccordance with the present invention provides not only bronchodilation,but also optionally improved heart function for a long enough period oftime that administered medication such as epinephrine has time to takeeffect before the patient suffocates. This is because the stimulating,blocking and/or modulating signal can also improve the heart function,by potentially elevating or decreasing heart rate.

Furthermore, as an option in the present invention, parameters of thestimulation may be modulated by the control unit 330 to control theimpulse generator 310 in such a way as to temporally modulatestimulation by the magnetic stimulator coil or electrodes, in such a wayas to achieve and maintain the heart rate within safe or desired limits.In that case, the parameters of the stimulation are individually raisedor lowered in increments (power, frequency, etc.), and the effect as anincreased, unchanged, or decreased heart rate is stored in the memory ofthe control unit 330. When the heart rate changes to a value outside thespecified range, the control unit 330 automatically resets theparameters to values that had been recorded to produce a heart ratewithin that range, or if no heart rate within that range has yet beenachieved, it increases or decreases parameter values in the directionthat previously acquired data indicate would change the heart rate inthe direction towards a heart rate in the desired range. Similarly, thearterial blood pressure is also recorded non-invasively in an embodimentof the invention, and as described above, the control unit 330 extractsthe systolic, diastolic, and mean arterial blood pressure from the bloodpressure waveform. The control unit 330 will then control the impulsegenerator 310 in such a way as to temporally modulate nerve stimulationby the magnetic stimulator coil or electrodes, in such a way as toachieve and maintain the blood pressure within predetermined safe ordesired limits, by the same method that was indicated above for theheart rate. Thus, even if one does not intend to treatbronchoconstriction, embodiments of the invention described above may beused to achieve and maintain the heart rate and blood pressure withindesired ranges.

Let the measured output variables of the system in FIG. 15 be denoted byy_(i) (i=1 to Q); let the desired (reference or setpoint) values ofy_(i) be denoted by r_(i) and let the controller's input to the systemconsist of variables u_(j) (j=1 to P). The objective is for a controllerto select the input u_(j) in such a way that the output variables (or asubset of them) closely follows the reference signals r_(i), i.e., thecontrol error e_(i)=r_(i)−y_(i) is small, even if there is environmentalinput or noise to the system. Consider the error functione_(i)=r_(i)−y_(i) to be the sensed physiological input to the controllerin FIG. 15 (i.e., the reference signals are integral to the controller,which subtracts the measured system values from them to construct thecontrol error signal). The controller will also receive a set ofmeasured environmental signals v_(k) (k=1 to R), which also act upon thesystem as shown in FIG. 15.

The functional form of the system's input u(t) is constrained to be asshown in FIGS. 2D and 2E. Ordinarily, a parameter that needs adjustingis the one associated with the amplitude of the signal shown in FIG. 2.As a first example of the use of feedback to control the system,consider the problem of adjusting the input u(t) from the vagus nervestimulator (i.e., output from the controller) in order to compensate formotion artifacts.

Nerve activation is generally a function of the second spatialderivative of the extracellular potential along the nerve's axon, whichwould be changing as the position of the stimulator varies relative tothe axon [F. RATTAY. The basic mechanism for the electrical stimulationof the nervous system. Neuroscience 89 (2, 1999):335-346]. Such motionartifact can be due to movement by the patient (e.g., neck movement) ormovement within the patient (e.g. sternocleidomastoid muscle contractionassociated with respiration), or it can be due to movement of thestimulator relative to the body (slippage or drift). Thus, one expectsthat because of such undesired or unavoidable motion, there will usuallybe some error (e=r−y) in the intended (r) versus actual (y) nervestimulation amplitude that needs continuous adjustment.

Accelerometers can be used to detect all these types of movement, usingfor example, Model LSM330DL from STMicroelectronics, 750 Canyon Dr #300Coppell, Tex. 75019. One or more accelerometer is attached to thepatient's neck, and one or more accelerometer is attached to the head ofthe stimulator in the vicinity of where the stimulator contacts thepatient. Because the temporally integrated outputs of the accelerometersprovide a measurement of the current position of each accelerometer, thecombined accelerometer outputs make it possible to measure any movementof the stimulator relative to the underlying tissue.

The location of the vagus nerve underlying the stimulator may bedetermined preliminarily by placing an ultrasound probe at the locationwhere the center of the stimulator will be placed [KNAPPERTZ V A,Tegeler C H, Hardin S J, McKinney W M. Vagus nerve imaging withultrasound: anatomic and in vivo validation. Otolaryngol Head Neck Surg118(1, 1998):82-5]. The ultrasound probe is configured to have the sameshape as the stimulator, including the attachment of one or moreaccelerometer. As part of the preliminary protocol, the patient withaccelerometers attached is then instructed to perform neck movements,breathe deeply so as to contract the sternocleidomastoid muscle, andgenerally simulate possible motion that may accompany prolongedstimulation with the stimulator. This would include possible slippage ormovement of the stimulator relative to an initial position on thepatient's neck. While these movements are being performed, theaccelerometers are acquiring position information, and the correspondinglocation of the vagus nerve is determined from the ultrasound image.With these preliminary data, it is then possible to infer the locationof the vagus nerve relative to the stimulator, given only theaccelerometer data during a stimulation session, by interpolatingbetween the previously acquired vagus nerve position data as a functionof accelerometer position data.

For any given position of the stimulator relative to the vagus nerve, itis also possible to infer the amplitude of the electric field that itproduces in the vicinity of the vagus nerve. This is done by calculationor by measuring the electric field that is produced by the stimulator asa function of depth and position within a phantom that simulates therelevant bodily tissue [Francis Marion MOORE. Electrical Stimulation forpain suppression: mathematical and physical models. Thesis, School ofEngineering, Cornell University, 2007; Bartosz SAWICKI, Robert Szmurto,Przemystaw Ptonecki, Jacek Starzyriski, Stanislaw Wincenciak, AndrzejRysz. Mathematical Modelling of Vagus Nerve Stimulation. pp. 92-97 in:Krawczyk, A. Electromagnetic Field, Health and Environment: Proceedingsof EHE'07. Amsterdam, IOS Press, 2008]. Thus, in order to compensate formovement, the controller may increase or decrease the amplitude of theoutput from the stimulator (u) in proportion to the inferred deviationof the amplitude of the electric field in the vicinity of the vagusnerve, relative to its desired value.

For present purposes, no distinction is made between a system outputvariable and a variable representing the state of the system. Then, astate-space representation, or model, of the system consists of a set offirst order differential equations of the form dy_(i)/dt=F_(i)(t,{y_(i)},{u_(j)},{v_(k)};{r_(i)}), where t is time andwhere in general, the rate of change of each variable y_(i) is afunction (F_(i)) of many other output variables as well as the input andenvironmental signals.

Classical control theory is concerned with situations in which thefunctional form of F_(i) is as a linear combination of the state andinput variables, but in which coefficients of the linear terms are notnecessarily known in advance. In this linear case, the differentialequations may be solved with linear transform (e.g., Laplace transform)methods, which convert the differential equations into algebraicequations for straightforward solution. Thus, for example, asingle-input single-output system (dropping the subscripts on variables)may have input from a controller of the form:

${u(t)} = {{K_{p}{e(t)}} + {K_{i}{\int_{0}^{t}{{e(\tau)}\ {\mathbb{d}\tau}}}} + {K_{d}\frac{\mathbb{d}e}{\mathbb{d}t}}}$where the parameters for the controller are the proportional gain(K_(p)), the integral gain (K_(i)) and the derivative gain (K_(d)). Thistype of controller, which forms a controlling input signal with feedbackusing the error e=r−y, is known as a PID controller(proportional-integral-derivative).

Optimal selection of the parameters of the controller could be throughcalculation, if the coefficients of the corresponding state differentialequation were known in advance. However, they are ordinarily not known,so selection of the controller parameters (tuning) is accomplished byexperiments in which the error e either is or is not used to form thesystem input (respectively, closed loop or open loop experiments). In anopen loop experiment, the input is increased in a step (or random binarysequence of steps), and the system response is measured. In a closedloop experiment, the integral and derivative gains are set to zero, theproportional gain is increased until the system starts to oscillate, andthe period of oscillation is measured. Depending on whether theexperiment is open or closed loop, the selection of PID parameter valuesmay then be selected according to rules that were described initially byZiegler and Nichols. There are also many improved versions of tuningrules, including some that can be implemented automatically by thecontroller [LI, Y., Ang, K. H. and Chong, G. C. Y. Patents, software andhardware for PID control: an overview and analysis of the current art.IEEE Control Systems Magazine, 26 (1, 2006): 42-54; Karl Johan Åström &Richard M. Murray. Feedback Systems: An Introduction for Scientists andEngineers. Princeton N.J.: Princeton University Press, 2008; FinnHAUGEN. Tuning of PID controllers (Chapter 10) In: Basic Dynamics andControl. 2009. ISBN 978-82-91748-13-9. TechTeach, Enggravhøgda 45,N-3711 Skien, Norway. http://techteach.no., pp. 129-155; Dingyu X U E,YangQuan Chen, Derek P. Atherton. PID controller design (Chapter 6), In:Linear Feedback Control: Analysis and Design with MATLAB. Society forIndustrial and Applied Mathematics (SIAM). 3600 Market Street, 6thFloor, Philadelphia, Pa. (2007), pp. 183-235; Jan JANTZEN, Tuning OfFuzzy PID Controllers, Technical University of Denmark, report 98-H 871,Sep. 30, 1998].

Commercial versions of PID controllers are available, and they are usedin 90% of all control applications. However, performance of systemcontrol can be improved by combining the feedback closed-loop control ofa PID controller with feed-forward control, wherein knowledge about thesystem's future behavior can be fed forward and combined with the PIDoutput to improve the overall system performance. For example, if thesensed environmental input in FIG. 15 is such the environmental input tothe system will have a deleterious effect on the system after a delay,the controller may use this information to provide anticipatory controlinput to the system, so as to avert or mitigate the deleterious effectsthat would have been sensed only after-the-fact with a feedback-onlycontroller. Because the present invention is concerned with anticipatingand averting acute medical events, the controller shown in FIG. 15 willgenerally make use of feed-forward methods [Coleman BROSILOW, BabuJoseph. Feedforward Control (Chapter 9) In: Techniques of Model-BasedControl. Upper Saddle River, N.J.: Prentice Hall PTR, 2002. pp,221-240]. Thus, the controller in FIG. 15 may be a type of predictivecontroller, methods for which have been developed in other contexts aswell, such as when a model of the system is used to calculate futureoutputs of the system, with the objective of choosing among possibleinputs so as to optimize a criterion that is based on future values ofthe system's output variables.

A mathematical model of the system is needed in order to perform thepredictions of system behavior. Models that are completely based uponphysical first principles (white-box) are rare, especially in the caseof physiological systems. Instead, most models that make use of priorstructural and mechanistic understanding of the system are so-calledgrey-box models, one of which is described below in connection with theforecasting of asthma attacks. If the mechanisms of the systems are notsufficiently understood in order to construct a white or grey box model,a black-box model may be used instead. Such models compriseautoregressive models [Tim BOLLERSLEV. Generalized autoregressiveconditional heteroskedasticity. Journal of Econometrics31(1986):307-327], or those that make use of principal components [JamesH. STOCK, Mark W. Watson. Forecasting with Many Predictors, In: Handbookof Economic Forecasting. Volume 1,G. Elliott, C. W. J. Granger and A.Timmermann, eds (2006) Amsterdam: Elsevier B. V, pp 515-554], Kalmanfilters [Eric A. WAN and Rudolph van der Merwe. The unscented Kalmanfilter for nonlinear estimation, In: Proceedings of Symposium 2000 onAdaptive Systems for Signal Processing, Communication and Control(AS-SPCC), IEEE, Lake Louise, Alberta, Canada, October, 2000, pp153-158], wavelet transforms [O. RENAUD, J.-L. Stark, F. Murtagh.Wavelet-based forecasting of short and long memory time series. SignalProcessing 48(1996):51-65], hidden Markov models [Sam ROWEIS and ZoubinGhahramani. A Unifying Review of Linear Gaussian Models. NeuralComputation 11(2, 1999): 305-345], or artificial neural networks[Guoquiang ZHANG, B. Eddy Patuwo, Michael Y. Hu. Forecasting withartificial neural networks: the state of the art. International Journalof Forecasting 14(1998): 35-62].

For the present invention, a grey-box model is preferred, but if ablack-box model must be used instead, the preferred model will be onethat makes use of support vector machines. A support vector machine(SVM) is an algorithmic approach to the problem of classification withinthe larger context of supervised learning. A number of classificationproblems whose solutions in the past have been solved by multi-layerback-propagation neural networks, or more complicated methods, have beenfound to be more easily solvable by SVMs. In the present context, atraining set of physiological data will have been acquired that includeswhether or not the patient is experiencing some type of acute attack.Thus, the classification of the patient's state is whether or not anattack is in progress, and the data used to make the classificationconsist of the remaining acquired physiological data, evaluated at Atime units prior to the time at which the attack data are acquired.Thus, the SVM is trained to forecast the imminence of an attack A timeunits into the future. After training the SVM, it is implemented as partof the controller to sound an alarm and advise the use of vagal nervestimulation, whenever there is a forecast of an imminent attack[Christopher J. C. BURGES. A tutorial on support vector machines forpattern recognition. Data Mining and Knowledge Discovery 2(1998),121-167; J. A. K. SUYKENS, J. Vandewalle, B. De Moor. Optimal Control byLeast Squares Support Vector Machines. Neural Networks 14 (2001):23-35;SAPANKEVYCH, N. and Sankar, R. Time Series Prediction Using SupportVector Machines: A Survey. IEEE Computational Intelligence Magazine 4(2,2009): 24-38; PRESS, W H; Teukolsky, S A; Vetterling, W T; Flannery, B P(2007). Section 16.5. Support Vector Machines. In: Numerical Recipes:The Art of Scientific Computing (3rd ed.). New York: CambridgeUniversity Press].

Although classical control theory works well for linear systems havingone or only a few system variables, special methods have been developedfor systems in which the system is nonlinear (i.e., the state-spacerepresentation contains nonlinear differential equations), or multipleinput/output variables. Such methods are important for the presentinvention because the physiological system to be controlled will begenerally nonlinear, and there will generally be multiple outputphysiological signals. It is understood that those methods may also beimplemented in the controller shown in FIG. 15 [Torkel GLAD and LennartLjung. Control Theory. Multivariable and Nonlinear Methods. New York:Taylor and Francis, 2000; Zdzislaw BUBNICKI. Modern Control Theory.Berlin: Springer, 2005].

Turning now to the use of feedback to control the system, consider theproblem of adjusting the input u(t) from the vagus nerve stimulator(i.e., output from the controller) in order to maintain the forcedexpiratory volume in one second (FEV₁) or an alternate lung functionindex FEV₁% VC at a predetermined value, using vagus nerve stimulation.Instead of using actual measurement of FEV₁, surrogate measurements ofFEV₁ can also be made, namely, pulsus paradoxus, accessory muscle use orairway resistance (Rint), as now described.

Three types of non-invasive measurements are currently recognized asbeing surrogates for the measurement of FEV1: pulsus paradoxus,accessory muscle use, and airway resistance. In the preferredembodiment, pulsus paradoxus is measured, which is based on theobservation that in asthmatic patients (as well as other patientsexperiencing bronchoconstriction), the patient's blood pressure waveformwill rise and fall as a function of the phase of respiration. In thepreferred embodiment, the blood pressure waveform (and the magnitude ofany accompanying pulsus paradoxus) is measured non-invasively with anarterial tonometer that is placed, for example, on the patient's wrist[James RAYNER, Flor Trespalacios, Jason Machan, Vijaya Potluri, GeorgeBrown, Linda M. Quattrucci, and Gregory D. Jay. Continuous NoninvasiveMeasurement of Pulsus Paradoxus Complements Medical Decision Making inAssessment of Acute Asthma Severity. CHEST 130(2006):754-765].Digitization and analysis of the blood pressure waveform may beperformed in a computer dedicated to that purpose, in which case, thenumerical value of the continuously varying pulsus paradoxus signalwould be transferred to the control unit 330 through a digital interfaceconnecting the control unit 330 and dedicated computer. Alternatively,the control unit 330 may contain an analog-to-digital converter toreceive the analog tonometric signal, and the analysis of the bloodpressure waveform would be performed within the control unit 330.Instead of using an arterial tonometer to measure the blood pressurewave form and any accompanying pulsus paradoxus, it is also possible touse a pulse oximeter, attached for example, to the patient's finger tip[Donald H ARNOLD, Cathy A Jenkins, Tina V Hartert. Noninvasiveassessment of asthma severity using pulse oximeter plethysmographestimate of pulsus paradoxus physiology. BMC Pulmonary Medicine10(2010):17; U.S. Pat. No. 7,044,917 and U.S. Pat. No. 6,869,402,entitled Method and apparatus for measuring pulsus paradoxus, toArnold]. A dedicated computer may be used to acquire and analyze theblood pressure waveform and the magnitude of pulsus paradoxus, whichwould be transferred to the control unit 330 as indicated above for thetonometrically acquired signal, or the analog pulse oximetry signal maybe digitized and processed within the control unit 330, as indicatedabove.

Accessory muscle use may also be used as a surrogate for the measurementof FEV1 [ARNOLD D H, Gebretsadik T, Minton P A, Higgins S, Hartert T V:Clinical measures associated with FEV1 in persons with asthma requiringhospital admission. Am J Emerg Med 25(2007): 425-429]. The accessorymuscles are not used during restful, tidal breathing of a normalpatient, but are used during labored breathing. The sternocleidomastoidmuscles are the most important accessory muscles of inspiration. Theyrun from the mastoid processes to insert along the medial third of theclavicle. To measure their use, a standard electromyogram may beperformed, the signal from which may be digitized and transferred to thecontrol unit 330 as indicated above [T. DE MAYO, R. Miralles, D.Barrero, A. Bulboa, D. Carvajal, S. Valenzuela, and G. Ormeno. Breathingtype and body position effects on sternocleidomastoid and suprahyoid EMGactivity. Journal of Oral Rehabilitation 32(7, 2005): 487-494; RobertoMERLETTI, Alberto Botter, Amedeo Troiano, Enrico Merlo, Marco AlessandroMinetto. Technology and instrumentation for detection and conditioningof the surface electromyographic signal: State of the art. ClinicalBiomechanics 24 (2009): 122-134]. Alternatively, non-invasiveplethysmography may be used to measure accessory muscle use, because asventilatory demands increase, these muscles contract to lift the sternumand increase the anteroposterior diameter of the upper rib cage duringinspiration. The anteroposterior diameter may be measured, for example,by respiratory inductance plethysmography (RIP) and electrical impedancetomography (EIT). RIP uses elastic bands around the chest (and abdomen)to assess changes in lung volume. EIT measures regional impedancechanges with electrodes around the patient's chest, each of theminjecting and receiving small currents. Such impedance changes have beencorrelated with dimensional changes of the lung. The plethysmographysignal may be digitized and transferred to the control unit 330 asindicated above, as a measure of the extent to which rib cage geometryis changing as the result of accessory muscle use.

Another surrogate for the measurement of FEV1 is the measurement ofairway resistance [P. D. BRIDGE, H. Lee, M. Silverman. A portable devicebased on the interrupter technique to measure bronchodilator response inschoolchildren. Eur Respir J 9(1996): 1368-1373]. Airway resistance isdefined as the ratio of the difference between mean alveolar pressureand airway opening pressure to flow measured at the mouth, and it may bemeasured using devices that are commercially available [e.g., MicroRint,Catalog No. MR5000 from Micromedical Ltd. and Cardinal Health UK 232Ltd, The Crescent, Jays Close, Basingstoke, RG22 4BS, U.K.]. Suchdevices have a serial or USB port that permits the control unit 330 toinstruct the device to perform the airway resistance measurement andreceive the airway resistance data in return, via a serial or USB portin the control unit 330. Because the measurement is necessarilyintermittent rather than continuous, and because it requires the patientto breathe passively through a mouthpiece or face mask, this surrogatefor the measurement of FEV1 is not the preferred one. For thosemeasurements that give intermittent readings, interpolation may be usedto construct a continuous surrogate signal of FEV1 (or other measuredsignals), which may be designated as the system output y(t).

The functional form of the system's input u(t) is constrained to be asshown in FIG. 2. Ordinarily, the parameter that needs adjusting is theone associated with the amplitude of the signal shown in FIG. 2, whichshould be increased or decreased to accommodate motion-related changesand drift. Rather than adjust the amplitude manually, one may use thePID that was described above, wherein the gains of the PID are tunedaccording to the Ziegler-Nichols or other rules. Thereafter, the PIDadjusts the amplitude automatically so as to best maintain the patient'sFEV₁ or surrogate value at a preferred value. The default amplitudeparameter is then reset according to its average value over time, as thePID continuously adjusts the value of the input u(t) thorough adjustmentof the stimulator signal's amplitude (and any other parameters that mayhave been tuned).

If feedforward rather than (or in addition to) feedback is to be used tocontrol the system, a feedforward model must be specified. Theparagraphs that follow describe such a feedforward model, which is basedon the observation that bronchial smooth muscle may be oscillating. Theproperties of oscillators are currently understood through the analysisof differential equation prototypes, such as Duffing's oscillator:

${{\frac{\mathbb{d}^{2}y}{\mathbb{d}t^{2}} + {m\frac{\mathbb{d}y}{\mathbb{d}t}} + \frac{\mathbb{d}P}{\mathbb{d}y}} = {f(t)}},$where y is the displacement of the oscillator (e.g., subtracted from avalue representing a time-averaged radius under normal conditions, y₀),m is a damping parameter, P is a potential function of y, and ƒ(t) is adriving function. In the case of respiration, the driving function wouldcorrespond to the flow of air as the respiratory muscles generateinspiration or relax for expiration, as well as the effects of localnerve fibers and circulating hormones on smooth muscle. The potentialfunction P(y) is often assumed to satisfy

${\frac{\mathbb{d}P}{\mathbb{d}y} = {{by} + {ay}^{3}}},$where a and b are constants

$\left( {{i.e.},{P = {{\frac{b}{2}y^{2}} + {\frac{a}{4}y^{4}}}}} \right),$which for a>0 and b<0 corresponds to a symmetric double-well potential.The potential may also be made asymmetric so that it is easier for theoscillator to reach one well than another, as in:

${P = {{\frac{b}{2}y^{2}} + {\frac{a}{4}y^{4}} + {y\left\lbrack {c + {{df}(t)}} \right\rbrack}}},$where c and d are parameters for asymmetry that is respectivelyindependent of, or dependent on, the driving function ƒ(t). In any case,two types of motion may be seen with such a double-well model: themotion can be confined to one of the wells when a weak driving functionƒ(t) is applied; or the oscillator can escape a well and visit the otherwell, and vice versa, when a stronger driving function ƒ(t) is applied[O. I. OLUSOLA, U. E. Vincent, A. N. Njah, and J. A. Olowofela.Bistability in coupled oscillators exhibiting synchronized dynamics.Commun. Theor. Phys. 53(2010), pp. 815-824]. If noise is added to thesystem it is possible to convert the former type of motion into thelatter, through a mechanism known as stochastic resonance [LucaGammaitoni, Peter Hänggi, Peter Jung, and Fabio Marchesoni. Stochasticresonance. Rev. Mod. Phys. 70(1998), 223-287].

Duffing's equation describes oscillations in the displacement y that arequalitatively different than those exhibited by a linear, harmonicdriven oscillator. Because it embodies a double-well potential, it isappropriate when a system is preferentially in one of two states, suchas a constricted state versus a dilated state, as in the case of abronchiole oscillator. If there were more than two preferential states,a potential having three or more wells may be assumed, as would be thecase if the bronchiole oscillator had relaxed, dilated, and intermediatestates. A network of coupled oscillators is constructed by making thedisplacement of one oscillator be a function of one or more of the otheroscillators' displacements, i.e., by coupling each oscillator to otheroscillators. Each oscillator in the network can in general havedifferent parameter values, and the network can have different forms oflocal or non-local coupling.

Other well-studied non-linear oscillators include Van der Pol,FitzHugh-Nagumo, Morris-Lecar, Ellias-Grossberg, and Stuart-Landau.Although the detailed oscillations described by such prototypicalequations are dependent on the detailed form of the equations and theirinitial conditions, the qualitative behaviors of such non-linear coupledoscillator equations may often be understood independently of theparticular form of the non-linear equation. For example, it is wellunderstood in general that non-linear oscillators, including a set ofcoupled non-linear oscillators, may exhibit qualitatively differentbehaviors when the parameters of their equations lie within certainbounds. When graphs are drawn showing the value of one parameter on oneaxis, and the value of another parameter on another axis, regions ofthis parameter space may be circumscribed to show what sets of parametervalues correspond to each type of qualitatively different dynamics,i.e., a phase diagram. Examples of such phase diagrams are given byMATTHEWS and STROGATZ, which circumscribe different regions of phasespace having qualitatively different dynamics, and which are alsodescribed below in connection with FIG. 16 [Paul C. MATTHEWS and StevenH. Strogatz. Phase diagram for the collective behavior of limit-cycleoscillators. Phys. Rev. Lett. 65(1990): 1701-1704].

When dealing with coupled nonlinear oscillators, such as coupled Duffingoscillators, the two or more oscillators may eventually all oscillatewith the same phase or they may prefer to oscillate with unrelatedphases, again depending on the range in which the parameter values lie.In the case of a two-well oscillator, the relation between the phase ofdifferent oscillators refers not only to simultaneously occurring peaksand valleys of displacement, but also whether oscillators aresimultaneously trapped in the same potential well. Chimera states, inwhich part of the system is phase locked and simultaneously another partof the system exhibits oscillators with unrelated phases, are alsopossible. Chimera states may be particularly significant in regards tothe regional inhomogeneity of the lung, when one portion of the lungexhibits unrelated phases, and another region exhibits phase locking.These qualitatively different types of dynamic behavior are influencedby the presence of noise, and they are exhibited by nonlinearoscillators generally, of which the Duffing oscillator is only oneexample [GUEVARA M. R. Bifurcations involving fixed points and limitcycles in biological systems. In: Nonlinear Dynamics in Physiology andMedicine, edited by Beuter A., Glass L., Mackey M. C., Titcombe M. S.Springer-Verlag, New York, pp. 41-85 (2003); LEE, Wai Shing; Restrepo,Juan G.; Ott, Edward; Antonsen, Thomas M. Dynamics and pattern formationin large systems of spatially-coupled oscillators with finite responsetimes. Chaos 21 (2, 2011), pp. 023122-023122-14; Hiroshi KORI andAlexander S. Mikhailov. Entrainment of Randomly Coupled OscillatorNetworks by a Pacemaker. Phys. Rev. Lett. 93(2004), 254101, pp 1-4; M.CISZAK, A. Montina, and F. T. Arecchi. Sharp versus smoothsynchronization transition of locally coupled oscillators. Phys. Rev. E78(2008), 016202, pp 1-4; Daniel M. ABRAMS and Steven H. Strogatz.Chimera States for Coupled Oscillators. Phys. Rev. Lett. 93(2004),174102, pp 1-4; KONISHI K. Experimental evidence for amplitude deathinduced by dynamic coupling: van der Pol oscillators. Proc. ISCAS (4,2004) 792-795; Shinji DOI, Yohei lsotani, Ken-ichiro Sugimoto andSadatoshi Kumagai. Noise-induced critical breakdown of phase lockings ina forced van der Pol oscillator. Physics Letters A 310 (5-6, 2003):407-414].

When one or more of the parameters of the set of coupled nonlinearoscillators may be varied under external influences to producequalitative changes of phase in the system, the parameter is said to bean order parameter. According to the present invention, bronchioles ofthe lung may be represented mathematically as nonlinear oscillators thatare coupled to one another, and an order parameter for the system is theconcentration of an environmental lung irritant, as shown in FIG. 16A.Another order parameter is related to the magnitude and duration ofvagus nerve stimulation, which will be described below. Consider firstonly the changes in phase that occur as the concentration of theirritant increases. Moving along the lower axis in FIG. 16A atincreasing irritant concentration, the successive phases that areencountered as the concentration is increased are called successively:phase drift, irregular region, and phase locked. The dynamics of thesystem in each of those phases is represented in FIG. 16B, in which theaverage, over multiple bronchioles, of bronchiole constriction is shownas a function of time. For present purposes, bronchial constriction maybe defined as the average of y₀/y, over many bronchioles, where y₀ is atime-averaged radius in a normal bronchiole and y is a bronchioledisplacement from that radius, such that as y becomes smaller, theconstriction becomes larger.

Within the phase drift phase, there are only small fluctuations ofconstriction amplitude averaged over many bronchioles. This correspondsto a situation in which the bronchioles are oscillating more or lessindependently of one another. Within the irregular phase, there aresmall fluctuations along with occasional irregularly-timed largeamplitude constrictions. The dynamics are not periodic, but may insteadexhibit aperiodic dynamics such as deterministic chaos, Hopfoscillation, quasiperiodicity, and large oscillation [Paul C. MATTHEWSand Steven H. Strogatz. Phase diagram for the collective behavior oflimit-cycle oscillators. Phys. Rev. Lett. 65(1990): 1701-1704; Paul C.MATTHEWS, Renato E. Mirollo, and Steven H. Strogatz. Dynamics of a largesystem of coupled nonlinear oscillators. Physica D: Nonlinear Phenomena52 (2-3, 1991): 293-331]. During the phase-locked phase, there are largeamplitude constrictions, as evidenced by the average of the displacementy over many bronchioles. In that phase, the constrictions correspond toalmost all bronchioles in some region(s) of the lung being trapped inone well of the double-well potential, namely, the well corresponding toa constricted bronchiole, as would occur in an asthma attack. However,the lung as a whole may also be in a chimera state, wherein some regionsof the lung are in one phase such as the phase-locked phase, while otherregions of the lung may be in some other phase such as the phase-driftphase, so that not all bronchioles of the lung need be constrictedduring an asthma attack.

Irritant concentrations may be measured non-invasively in real time foran ambulatory patient [Kirk J. ENGLEHARDT and John Toon. Asthma attack:Vest-based sensors monitor environmental exposure to help understandcauses: web page (www) at the Georgia Tech Research Institute (.gtri) ofGeorgia Tech (.gatech) educational domain (.edu) in subdomain:/casestudy/asthma-vest-helps-id-asthma-causes; patent applicationUS20110144515, entitled Systems and methods for providing environmentalmonitoring, to BAYER et al.; and U.S. Pat. No. 7,119,900, entitledPollen sensor and method, to OKUMURA et al]. For physical externalirritants, the unit of irritation should be selected accordingly, suchas temperature for cold air as an irritant.

It is understood, however, that in some patients, external irritanttriggers are hard to identify, and some irritant triggers may well beendogenous substances. In that case, according to the invention, asurrogate for an unknown or endogenous trigger concentration may be theconcentration of exhaled nitric oxide, which can be measurednoninvasively using miniature gas sensors placed in the vicinity of thepatient's mouth [GILL M, Walker S, Khan A, Green S M, Kim L, Gray 5,Krauss B. Exhaled nitric oxide levels during acute asthma exacerbation.Acad Emerg Med 12(7, 2005):579-86; Oleksandr KUZMYCH, Brett L Allen andAlexander Star. Carbon nanotube sensors for exhaled breath components.Nanotechnology 18 (2007) 375502, pp 1-7]. Accordingly, what is labeledas “Concentration of Environmental Irritants” in FIG. 16 may be replacedby the concentration of any other exogenous or endogenous trigger, or bya surrogate for an asthma trigger.

Referring again to the phase diagram in FIG. 16A, note that the verticalaxis is labeled as “Accumulated Vagus Nerve Stimulation Effects.”According to the present invention, the effectiveness of vagus nervestimulation in inhibiting bronchiole constriction is a function of theelectric field produced by the stimulation and its waveform, theduration of the stimulation, and if stimulation has ceased, the timesince cessation of the last stimulation. Let the numerical value of theaccumulated “Accumulated Vagus Nerve Stimulation Effects” with aparticular stimulation waveform be denoted as S(t). It may for presentpurposes be represented as a function that increases at a rateproportional to the stimulation electric field V at the site of thenerve and decays with a time constant τ_(P), such that after prolongedstimulation, the accumulated stimulation effectiveness will saturate ata value equal to the product of V and τ_(P). Thus, if T_(p) is theduration of a vagal nerve stimulation, then for time t<T_(P),S(t)=Vτ_(P)[1−exp(−t/τ_(P))]+S₀ exp(−t/τ_(P)), and for t>T_(P),S(t)=S(T_(P))exp(−[t−T_(P)]/τ_(P)), where the time t is measured fromthe start of a stimulus, and S₀ is the value of S when t=0. Then,according to FIG. 16, as electrical stimuli to the vagus nerve areapplied, it is possible for the lung system as a whole to switch fromone phase of bronchial constriction to another, even if the lung isexposed to a constant irritant environment.

For example, if the system begins in the phase locked phase shown inFIG. 16A (asthma attack), it can be simulated up and out of that phaseinto the phase drift phase, and after stimulus ceases, the system willeventually decay back into the phase locked phase (assuming that thepatient's physiology remains stationary). The situation with any givenindividual would depend upon that individual's particular phase diagram,but if the individual has a diagram like the one shown in FIG. 16A, thenthe best strategy for preventing or terminating unwantedbronchoconstriction would be to stimulate the vagus nerve for as long aspossible with as high an electric field as possible, so as to drive thesystem out of its current phase and into the phase drift phase (ormaintain it in the drift phase) for as long as possible. However, thatstrategy may not be practical, because at some electric field, thestimulus would be too painful and would produce side-effects. In anyevent the vagus nerve stimulation is not intended to be continuous, ascould have been the case with an implanted stimulator. Furthermore,because of decay of the accumulated stimulus effect, additionalstimulation may be increasingly ineffective as the effect saturates at alevel determined by the stimulation electric field V and decay timeconstant τ_(P).

Implementation of this model of an asthma attack requires a moredetailed mathematical embodiment of the invention. For example, in oneembodiment, the bronchiole oscillators are represented as coupledDuffing oscillators, as in the following equations with two oscillators.Such a representation can be expanded to any number of oscillators bymaking all oscillators coupled to all other oscillators so as toemphasize neural or humoral feedback loops, or only to oscillators(bronchioles) in proximity to one another so as to emphasize localnearest-neighbor effects, or some intermediate coupling configuration.

${\frac{\mathbb{d}^{2}y_{1}}{\mathbb{d}t^{2}} + {m_{1}\frac{\mathbb{d}y_{1}}{\mathbb{d}t}} + \frac{\mathbb{d}P_{1}}{\mathbb{d}y_{1}}} = {f_{1}(t)}$and${{\frac{\mathbb{d}^{3}y_{2}}{\mathbb{d}t^{2}} + {m_{2}\frac{\mathbb{d}y_{2}}{\mathbb{d}t}} + \frac{\mathbb{d}P_{2}}{\mathbb{d}y_{2}}} = {f_{2}(t)}},$where y₁ and y₂ are the radii of sister branches of bronchioles relativeto an offset y₀. For example, the bronchioles may be between the fourthand eighth bronchial bifurcations. One form of coupling is through thefact that a flow ƒ(t) through the parent bronchiole of bronchioles 1 and2 is ƒ(t)=ƒ₁(t)+ƒ₂(t), so that if one sister bronchiole constricts andthe other sister bronchiole does not, the flow ƒ(t) will bepreferentially distributed to the latter bronchiole. For purposes ofestimating the flows, it is assumed that nasal and/or oral airflow ismeasured (e.g., with thermistors) in conjunction with respiratoryinductive plethysmography, mercury in silastic strain gauges orimpedance pneumography so as to measure total respiratory air flow,which can be calibration with a spirometer. Assuming that the lengths ofthe bronchi and bronchioles are the same at any corresponding level ofbranching, assuming the validity of Ohm's law and Poiseuille's law, andgiven the measured total air flow, the values of the driving flows ƒ₁(t)and ƒ₂(t) can be estimated for the current values of y₁ and y₂. Similarequations are written for the multiple levels of bronchiolebifurcations. Because flow at one level of bronchiole branching caninfluence flow that is connected to it at another level, the equationsfor the bronchiole oscillators are therefore coupled to one another atleast by virtue of the anatomy of the lung and flow within the branchingbronchioles.

According to the invention, the presence of irritant in the airstream ofany bronchiole (or other trigger surrogate) is accounted for by makingparameters describing the potential P be a function of the flow andconcentration of environmental irritant. For example, with theasymmetric potential

${P = {{\frac{b}{2}y^{2}} + {\frac{a}{4}y^{4}} + {y\left\lbrack {c + {{df}(t)}} \right\rbrack}}},$where d is a parameter that is a function of irritant concentration, thesystem would preferentially constrict the bronchiole on inspiration(positive ƒ, preventing the irritant from reaching the alveoli) andpreferentially dilate the bronchiole on expiration (negative ƒ, allowingthe irritant to be expelled from the alveoli). If K is the irritantconcentration, then for example, the dependence of parameter d on K maybe expressed as d=d₀+d₁K+d₂K²+ . . . .

An increase in the parameter c would increase the stability of thepotential well corresponding to bronchoconstriction, independently ofany changes in the flow. Accordingly, stimulation of the bronchioles byhistamine, the parasympathetic nervous system, or any other factor thatpromotes bronchoconstriction should be accompanied by an increase in theparameter c. Conversely, a decrease in the parameter c would increasethe stability of the potential well corresponding to bronchodilation.Accordingly, stimulation of the bronchioles by epinephrine, thesympathetic nervous system, or any other factor that promotesbronchodilation should be accompanied by a decrease in the parameter c.For example, one may write c as c=c_(c)−c_(d), where an increase inc_(c) caused bronchoconstriction and an increase in c_(d) causesbronchodilation. Then, the vagal nerve stimulation S(t), which wasdefined above, may be introduced through the parameter c_(d). Forexample,a=a ₀₀ +a ₁₀ U+a ₀₁ S+a ₁₁ US+a ₂₀ U ² +a ₀₂ S ² + . . . =c _(d0) +c_(d1) S+c _(d2) S ²+ . . . .

Breathing is to some extent under voluntary control, so that anindividual can deliberately vary the driving function ƒ(t). On the otherhand, breathing is also to some extent involuntary and controlled by thenervous system. Accordingly, one may expand the above model to accountfor respiratory reflexes [H. T. MILHORN Jr., R. Benton, R. Ross, and A.C. Guyton. A mathematical model of the human respiratory control system.Biophys J. 5(1965):27-46]. To do so, the coupling parameter(s) may alsobe made to be a function of multiple oscillator values, possibly at aprevious time t-A, so as to account for the time delay A in neuralreflexes between afferent signals and efferent effects that coupleoscillators to one another. Such an expanded neural control model may beused to forecast ƒ(t), or alternatively, non-physiological models may beused to forecast future values of ƒ(t) based on previous values of ƒ(t)[CAMINAL P, Domingo L, Giraldo B F, Vallverdú M, Benito S, Vazquez G,Kaplan D. Variability analysis of the respiratory volume based onnon-linear prediction methods. Med Biol Eng Comput 42(1, 2004):86-91].It is understood that additional extensions of the above dynamical modelmay make the anatomy and physiology more complete, accurate or detailed;for example, one may wish to create a more realistic model of thepatient's lung anatomy than what was described above [LEE, S. L. A.;Kouzani, A. Z.; Hu, E. J.; From lung images to lung models: A review.IEEE International Joint Conference on Neural Networks 2008: 2377-2383].

Usefulness of this method is dependent on the extent to which thepatient is willing to undergo measurement to allow estimation of anembodiment of the equations' parameters. It is understood that themeasurement will consist of a period of baseline monitoring, followed bya period during which the vagus nerve is stimulated using a defaultstimulation protocol or during which vagal nerve stimulation parametersare varied. The most useful measurements would be ones in which nearbygroups of bronchioles are measured separately, so as to be able toestimate parameters separately for those localized groups ofoscillators. This will require imaging of the lung in order to evaluatethe spatial heterogeneity of bronchiolar constriction.

Many methods exist for the noninvasive imaging of the lung. However, thenoninvasive imaging methods that are preferred here are those that maybe performed by continuous noninvasive ambulatory monitoring. At thepresent time, the preferred imaging methods comprise electricalimpedance tomography and acoustic imaging. Electrical impedancetomography (EIT) is an imaging technique in which an image of theconductivity of the chest is inferred from surface electricalmeasurements. To perform EIT, conducting electrodes are attached to theskin of the patient and small alternating currents are applied to someor all of the electrodes. The resulting electrical potentials aremeasured, and the process may be repeated for numerous differentconfigurations of applied current. A calculation is then performed toinfer the lung structure that could have given rise to the measuredelectrical potentials [David HOLDER. Electrical impedance tomography:methods, history, and applications. Institute of Physics Publishing,Bristol and Philadelphia, 2005; WENG T R, Spence J A, Polgar G, NyboerJ. Measurement of regional lung function by tetrapolar electricalimpedance plethysmography. Chest 76(1, 1979):64-9; FRERICHS I.Electrical impedance tomography (EIT) in applications related to lungand ventilation: a review of experimental and clinical activities.Physiol Meas. 21(2, 2002):R1-21; FRERICHS I, Hinz J, Herrmann P, WeisserG, Hahn G, Dudykevych T, Quintel M, Hellige G. Detection of local lungair content by electrical impedance tomography compared with electronbeam CT. J Appl Physiol 93(2, 2002):660-6; J. KARSTEN, T. Meier, H.Heinze. Bedside-measurements of electrical impedance tomography andfunctional residual capacity during positioning therapy in a case ofacute respiratory failure Applied Cardiopulmonary Pathophysiology,15(2011): 81-86; FAGERBERG A, Söndergaard S, Karason S, Aneman A.Electrical impedance tomography and heterogeneity of pulmonary perfusionand ventilation in porcine acute lung injury. Acta Anaesthesiol Scand.2009 November; 53(10):1300-9].

The other noninvasive ambulatory imaging method, acoustic imaging,involves the placement of multiple microphones on the patient's chestand back. It is particularly useful to detect and localize groups ofbronchioles that have abruptly opened and made a corresponding sound[KOMPIS M, Pasterkamp H, Wodicka G R. Acoustic imaging of the humanchest. Chest 120(4, 2001):1309-21; PASTERKAMP H, Kraman S S, Wodicka GR. Respiratory sounds. Advances beyond the stethoscope. Am J Respir CritCare Med 156(3 Pt 1, 1997):974-87; Adriano M. ALCENAR, Arnab Majumdar,Zoltan Hantos, Sergey V. Buldyrev, H. Eugene Stanley, Bela Suki.Crackles and instabilities during lung inflation. Physica A: StatisticalMechanics and its Applications 357(1, 2005): 18-26].

In addition to these noninvasive measurements, as well as conventionalambulatory measurements for breathing, heart rate, and the like, onewould preferably use an accelerometer and/or inclinometer so as toaccount for changes in lung anatomy and physiology as the patientchanges posture or moves about [GALVIN I, Drummond G B, Nirmalan M.Distribution of blood flow and ventilation in the lung: gravity is notthe only factor. Br J Anaesth 98(4, 2007):420-8]. The sensors may beembedded in garments or placed in sports wristwatches, as currently usedin programs that monitor the physiological status of soldiers [G. A.Shaw, A. M. Siegel, G. Zogbi, and T. P. Opar. Warfighter physiologicaland environmental monitoring: a study for the U.S. Army ResearchInstitute in Environmental Medicine and the Soldier Systems Center. MITLincoln Laboratory, Lexington Mass. 1 Nov. 2004, pp. 1-141].

Estimation of parameters of the equations from continuously acquireddata may be made using existing methods such as the multiple shootingand recursive (e.g., Kalman filter) approaches [Henning U. VOSS and JensTimmer. Nonlinear dynamical system identification from uncertain andindirect measurements. International Journal of Bifurcation and Chaos14(6, 2004):1905-1933], or synchronization methods [H D I ABARBANEL, D RCreveling, and J M Jeanne. Estimation of parameters in nonlinear systemsusing balanced synchronization. Physical Review E 77(2008):016208, pp1-14]. As the patient's ambulatory data evolve in time, the estimatedparameters may also evolve in time and must be updated.

After parameter estimation, numerical simulation with thecoupled-oscillator equations into the future may forecast the imminentonset of an asthma attack, i.e., an abrupt transition wherein groups ofbronchioles constrict (see FIG. 16). It is understood that thesimulation must occur at a rate that is significantly faster than actualtime, otherwise there would be little warning for the patient. When sucha warning is given, the patient or a caregiver would perform vagus nervestimulation as described above in order to avert the asthma attack.

For situations in which it is impractical to use the above gray-boxmodel of asthma, for example, if the patient is unwilling to wear theelectrical impedance tomography and acoustic imaging sensors formeasuring respiratory heterogeneity, then one may instead use theblack-box approach that was described above, using the remaining sensors(respiration, environmental sensors, etc.). In that case, the patientwould mark the onset of an asthma attack with an event button, and theset of ambulatory measurements would be used to train a support vectormachine classifier model. After training, that model could be used toforecast the asthma attack and advise the patient to perform vagus nervestimulation, or to select stimulation parameters so as to most rapidlyterminate an ongoing bronchoconstrictive exacerbation.

In another aspect of the invention, the applicant has discovered thatmany seemingly disparate disorders may, in fact, have common causes thatmanifest into different symptoms or disorders in different individuals.Specifically, the applicant has discovered that in certain individualswho may suffer from disorders, such as depression, asthma, COPD,migraine, cluster headache, anxiety, fibromyalgia, epilepsy and thelike, certain areas of the brain are prone to periodic or continuousexcessive excitatory neurotransmitter levels. These periodic excessiveexcitatory neurotransmitter levels can be caused by certain “triggers”,such as noxious substances entering the lungs that cause airwayreactivity or other triggers, such as chocolate or seafood that cancause migraines in certain individuals. In other cases, the patient mayhave pathologically high excitatory neurotransmitter levels on acontinuous basis without any particular trigger. One example, of anexcitatory neurotransmitter is glutamate, which is known to beassociated with migraines.

The excessive excitatory neurotransmitter levels in a patient's braincan be caused by inaccurate signals from the body transmitted throughthe vagus nerve or other nerves or these excessive levels can be causedby the brain overreacting to normal signals coming from the body. Insome cases, these excessive excitatory neurotransmitter levels may becaused by inappropriate inactivity in the production and/or release ofinhibitory neurotransmitters, such as GABA, serotonin and/ornorepinephrine. A reduced level of these inhibitory neurotransmitterlevels can result in excessive levels of the excitatoryneurotransmitters that they are meant to balance.

The present invention seeks to address this imbalance inneurotransmitters in the brain that can result in many of the disordersmentioned above. Specifically, afferent nerve fibers in the vagus nerveare stimulated with the devices, signals and methods described above toheighten activity in areas of the brain (e.g., the periaqueducatal gray,locus ceruleus and/or raphe nuclei) resulting in the release ofinhibitory neurotransmitter levels, such as GABA, norephinephrine and/orserotonin). For example, as discussed above, heightened activity in thelocus coeruleus will result in a release of norephinephrine or anincrease the release of norephinephrine. This release of inhibitoryneurotransmitters suppresses the excessive excitatory neurotransmittersand creates balance in the brain such that the brain either does notoverreact to certain stimuli and/or to modulate the pathologically highlevel of excitatory neurotransmitters.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

The invention claimed is:
 1. A method of treating a breathing disorderin a patient, the method comprising: positioning a handheld devicecomprising a housing comprising an electrically conductive contactingsurface, a power source, an electrode, and a conductive gel, wherein theelectrode is coupled to the power source, wherein the housing isadjacent to a skin surface of the patient, wherein the conductive gelcouples the electrode to the electrically conductive contacting surface;generating, via the device, a signal comprising one or more electricalimpulses; and transmitting, via the device, the one or more electricalimpulses to a vagus nerve in the patient, wherein the one or moreelectrical impulses comprises bursts of pulses with a silent inter-burstinterval between each of the bursts, wherein each of the bursts and thesilent inter-burst interval repeats from about 3 Hz to about 100 Hz,wherein each of the pulses has a duration from about 50 microseconds toabout 1000 microseconds.
 2. The method of claim 1, wherein the one ormore electrical impulses is sufficient to activate neural pathways thatreduce a release of acetycholine from airway-related vagal preganglionicneurons within a brain of the patient.
 3. The method of claim 2, furthercomprising: generating, via the device, an electric field at the vagusnerve, wherein the electric field is above a threshold for generatingaction potentials within fibers of the vagus nerve responsible foractivating the neural pathways that reduce the release of acetycholinefrom the airway-related vagal preganglionic neurons.
 4. The method ofclaim 3, wherein the electric field is below a threshold for generatingaction potentials within fibers of the vagus nerve responsible forbronchoconstriction.
 5. The method of claim 3, wherein the electricfield is below a threshold for generating action potentials withinfibers of the vagus nerve responsible for increasing or decreasing heartrate or blood pressure.
 6. The method of claim 1, wherein the one ormore electrical impulses is sufficient to activate neural pathways thatreduce mucous production in mucous glands in air passages in thepatient.
 7. The method of claim 3, wherein the electric field at thevagus nerve is above a threshold for generating action potentials withinfibers of the vagus nerve responsible for activating the neural pathwaysthat cause a release of inhibitory neurotransmitters within the brain ofthe patient.
 8. The method of claim 7, wherein at least one of theinhibitory neurotransmitters is at least one of serotonin, GABA, andnorepinephrine.
 9. The method of claim 1, wherein the power sourcecomprises a signal generator.
 10. A handheld device for treating abreathing disorder in a patient, the device comprising: a housingcomprising an electrically conducting contact surface, an energy source,an electrode, and a conductive gel, wherein the electrode is coupled tothe energy source, wherein the conductive gel couples the electrode tothe electrically conducting contact surface, wherein the electricallyconducting contact surface is configured to contact an outer skinsurface of the patient, wherein the energy source is configured totransmit an electric current through the outer skin surface of thepatient to a vagus nerve within the patient, wherein the electriccurrent is sufficient to generate a signal comprising one or moreelectrical impulses comprising bursts of pulses with a silentinter-burst interval between each of the bursts, wherein each of thebursts and the silent inter-burst interval repeats from about 3 Hz toabout 100 Hz, and wherein each of the pulses has a duration from about50 microsecond to about 1000 microseconds.
 11. The device of claim 10,wherein the one or more electrical impulses is sufficient to activateneural pathways that reduce a release of acetylcholine fromairway-related vagal preganglionic neurons within a brain of thepatient.
 12. The device of claim 11, wherein the energy source isconfigured to generate an electric field at the vagus nerve, wherein theelectric field is above a threshold for generating action potentialswithin fibers of the vagus nerve responsible for activating the neuralpathways that reduce the release of acetylcholine from theairway-related vagal preganglionic neurons.
 13. The device of claim 10,wherein the electric current is below a threshold for generating actionpotentials within fibers of the vagus nerve responsible forbronchoconstriction.
 14. The device of claim 10, wherein the electriccurrent is below a threshold for generating action potentials withinfibers of the vagus nerve responsible for modulating heart rate or bloodpressure.
 15. The device of claim 10, wherein the electric current issufficient to activate neural pathways that reduce mucous production inmucous glands in air passages in the patient.
 16. The device of claim10, wherein the electric current is from about 10 V/m to about 600 V/m.17. The device of claim 10, wherein the electric current is sufficientto generate an electric field gradient at the vagus nerve, wherein theelectric field gradient is greater than about 2 V/m/mm.
 18. The deviceof claim 10, wherein the electric current is less than about 100 V/m.19. The device of claim 10, wherein the energy source comprises a signalgenerator and one or more electrodes coupled to the signal generatorwithin the housing.
 20. The device of claim 10, wherein the energysource comprises a battery.